3-oxo-6-heteroaryl-2-phenyl-2,3-dihydropyridazine-4-carboxamides

ABSTRACT

The present invention covers 3-oxo-6-heteromyl-2-phenyl-2,3-dihydropyri-dazine-4-carboxamide compounds of general formula (I): in which R 1 , R 2 , R 4 , R 5 , R 6 , X, Y and Z are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.

The present invention covers3-oxo-6-heteroaryl-2-phenyl-2,3-dihydropyridazine-4-carboxamidecompounds of general formula (I) as described and defined herein,methods of preparing said compounds, intermediate compounds useful forpreparing said compounds, pharmaceutical compositions and combinationscomprising said compounds, and the use of said compounds formanufacturing pharmaceutical compositions for the treatment orprophylaxis of diseases, in particular cancer or conditions withdysregulated immune responses, as a sole agent or in combination withother active ingredients.

BACKGROUND

The AHR (Aryl Hydrocarbon Receptor) is a ligand-activated transcriptionfactor, belonging to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS)family, and is located in the cytosol. Upon ligand binding, the AHRtranslocates to the nucleus where it heterodimerises with ARNT (AHRNuclear Translocator) upon which it interacts with DREs (Dioxin ResponseElements) of AHR-responsive genes to regulate their transcription. TheAHR is best known for binding to environmental toxins and inducing themetabolic machinery, such as cytochrome P 450 enzymes (e.g. CYP1A1,CYP1A2 and CYP1B1), required for their elimination (Reyes et al.,Science, 1992, 256(5060):1193-5). Activation of AHR by xenobiotics hasdemonstrated its role in numerous cellular processes such asembryogenesis, tumourigenesis and inflammation. AHR is expressed in manycells of the immune system, including dendritic cells (DCs),macrophages, T cells and NK cells, and plays an important role inimmunoregulation (Nguyen et al., Front Immunol, 2014, 5:551). Theclassic exogenous AHR ligands TCDD and 3-methylcholanthrene, forexample, are known to induce profound immunosuppression, promotecarcinogenesis and induce tumour growth (Gramatzki et al., Oncogene,2009, 28(28):2593-605; Bui et al., Oncogene, 2009, 28(41):3642-51; Esseret al., Trends Immunol, 2009, 30:447-454). In the context ofimmunosuppression, AHR activation promotes regulatory T cell generation,inhibits Th1 and Th17 differentiation, directly and indirectly, anddecreases the activation and maturation of DCs (Wang et al., Clin ExpImmunol, 2014, 177(2):521-30; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Wei et al., Lab Invest, 2014, 94(5):528-35; Nguyen et al., PNAS,2010, 107(46):19961-6). AHR activation modulates the innate immuneresponse and constitutive AHR expression has been shown to negativelyregulate the type-I interferon response to viral infection (Yamada etal., Nat Immunol, 2016). Additionally, mice with a constitutively activeAHR spontaneously develop tumours (Andersson et al., PNAS, 2002,99(15):9990-5).

In addition to xenobiotics, the AHR can also bind metabolic products oftryptophan degradation. Tryptophan metabolites, such as kynurenine andkynurenic acid, are endogenous AHR ligands that activate the AHR underphysiological conditions (DiNatale et al., Toxicol Sci, 2010,115(1):89-97; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Opitz etal., Nature, 2011, 478(7368):197-203). Other endogenous ligands areknown to bind the AHR although their physiological roles are currentlyunknown (Nguyen & Bradfield, Chem Res Toxicol, 2008, 21(1):102-116).

The immunosuppressive properties of kynurenine and tryptophandegradation are well described and are implicated in cancer-associatedimmunosuppression. The enzymes indoleamine-2,3-dioxygenases 1 and 2(IDO1/ID02) as well as tryptophan-2,3-dioxygenase 2 (TDO2) areresponsible for catalysing the first and rate-limiting step oftryptophan metabolism. IDO1/2-mediated degradation of tryptophan intumours and tumour-draining lymph nodes reduces anti-tumour immuneresponses and inhibition of IDO can suppress tumour formation in animalmodels (Uyttenhove et al., Nat Med, 2003, 9(10):1269-74 ; Liu et al.,Blood, 2005, 115(17): 3520-30; Muller et al., Nat Med, 11(3):312-9;Metz, Cancer Res, 2007, 67(15):7082-7).

TDO2 is also strongly expressed in cancer and can lead to the productionof immunosuppressive kynurenine. In glioma, activation of the AHR bykynurenine, downstream of TDO-mediated tryptophan degradation, enhancestumour growth as a consequence of inhibiting anti-tumour immuneresponses as well as directly promoting tumour cell survival andmotility (Opitz et al., Nature, 2011, 478(7368):197-203). AHR ligandsgenerated by tumour cells therefore act in both an autocrine andparacrine fashion on tumour cells and lymphocytes, respectively, topromote tumour growth.

The present invention covers3-oxo-6-heteroaryl-2-phenyl-2,3-dihydropyridazine-4-carboxamidecompounds of general formula (I) which inhibit the AHR.

STATE OF THE ART

WO 2010/059401 relates to compounds and compositions for expanding thenumber of CD34+ cells for transplantation. In particular, WO 2010/059401relates inter alia to heterocyclic compounds capable of down-regulatingthe activity and/or expression of AHR.

WO 2012/015914 relates to compositions and methods for modulating AHRactivity. In particular, WO 2012/015914 relates inter alia toheterocyclic compounds that modulate AHR activity for use in therapeuticcompositions.

WO 2007/058392 relates to novel heterocyclic compounds and apharmaceutical use thereof. In particular, WO 2007/058392 relates interalia to heterocyclic compounds having an hepatitis C virus cellinfection inhibitory activity.

WO 2002/022587 relates to novel compounds exhibiting inhibitoryactivities against AMPA receptor and/or kainate receptor. In particular,WO 2002/022587 relates inter alia to pyridazinone and triazinonecompounds.

U.S. Pat. No. 5,418,233 relates to heterobiaryl derivatives inhibitingcell-cell aggregation and cell-matrix interactions. In particular, U.S.Pat. No. 5,418,233 relates to heterobiaryl derivatives which arehistamine receptor antagonists.

WO 2015/143164 relates to antimicrobial agents and screening methods. Inparticular, WO 2015/143164 relates inter alia to pyridazinone compoundsas antibiotics.

WO 2009/142732 relates to substituted pyridazinone derivatives and theiruse as H₃ antagonists/inverse agonists.

However, the state of the art does not describe the3-oxo-6-heteroaryl-2-phenyl-2,3-dihydropyridazine-4-carboxamidecompounds of general formula (I) of the present invention as describedand defined herein.

It has now been found, and this constitutes the basis of the presentinvention, that the compounds of the present invention have surprisingand advantageous properties.

In particular, the compounds of the present invention have surprisinglybeen found to effectively inhibit AHR for which data are given inbiological experimental section and may therefore be used for thetreatment or prophylaxis of cancer or other conditions where exogenousand endogenous AHR ligands induce dysregulated immune responses,uncontrolled cell growth, proliferation and/or survival of tumour cells,immunosuppression in the context of cancer, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ordiseases which are accompanied with uncontrolled cell growth,proliferation and/or survival of tumour cells, immunosuppression in thecontext of cancer inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival of tumour cells,immunosuppression in the context of cancer, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by AHR, such as, for example, liquid and solid tumours, and/ormetastases thereof, e.g. head and neck tumours including brain tumoursand brain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours including colon,colorectal and pancreatic tumours, liver tumours, endocrine tumours,mammary and other gynecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

-   in which-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   4- to 6-membered heterocycloalkyl substituted once with hydroxy        or C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (4- to 6-membered heterocycloalkyl substituted once with        hydroxy)-C₁-C₄-alkyl;-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, halogen or cyano;-   R⁵ represents hydrogen or halogen;-   R⁶ represents hydrogen or halogen;-   R⁷ represents C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, 4- to 6-membered    heterocycloalkyl, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano or —NR⁸R⁹;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R10 represents hydrogen or C₁-C₄-alkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

Further, it covers their use in combination with other anti cancermedications such as immunotherapeutics, targeted anti cancer agents orchemotherapy.

Definitions

The term “substituted” means that one or more hydrogen atoms on thedesignated atom or group are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded. Combinations ofsubstituents and/or variables are permissible.

The term “optionally substituted” means that the number of substituentscan be equal to or different from zero. Unless otherwise indicated, itis possible that optionally substituted groups are substituted with asmany optional substituents as can be accommodated by replacing ahydrogen atom with a non-hydrogen substituent on any available carbonatom. Commonly, it is possible for the number of optional substituents,when present, to be 1, 2 or 3.

The term “comprising” when used in the specification includes“consisting of”.

If within the present text any item is referred to as “as mentionedherein”, it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:

The term “halogen” means a fluorine, chlorine, bromine or iodine,particularly a fluorine, chlorine or bromine atom.

The term “C₁-C₆-alkyl” means a linear or branched, saturated, monovalenthydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or1,3-dimethylbutyl group, or an isomer thereof. Particularly, said grouphas 1, 2, 3 or 4 carbon atoms (“C₁-C₄-alkyl”), e.g. a methyl, ethyl,propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, moreparticularly 1, 2 or 3 carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl,ethyl, n-propyl or isopropyl group.

The term “C₂-C₈-alkyl” means a linear or branched, saturated, monovalenthydrocarbon group having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. aethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 3-ethyl-pentyl or 3-ethyl-hexyl group, or an isomerthereof. Particularly, said group has 2, 3 or 4 carbon atoms(“C₂-C₄-alkyl”), e.g. a ethyl, propyl, isopropyl, butyl, sec-butylisobutyl, or tert-butyl group, more particularly 2 or 3 carbon atoms(“C₂-C₃-alkyl”), e.g. a ethyl, n-propyl or isopropyl group.

The term “C₂-C₈-hydroxyalkyl” means a linear or branched, saturated,monovalent hydrocarbon group in which the term “C₂-C₈-alkyl” is definedsupra, and in which 1 or 2 hydrogen atoms are replaced with a hydroxygroup, e.g. a 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl,2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl,3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl,1-hydroxy-2-methyl-propyl, 3-ethyl-2-hydroxypentyl or3-ethyl-2-hydroxyhexyl group.

The term “C₁-C₄-alkoxy” means a linear or branched, saturated,monovalent group of formula (C₁-C₄-alkyl)-O—, which means methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy ortert-butoxy.

The term “C₃-C₆-cycloalkyl” means a saturated, monovalent, monocyclichydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms(“C₃-C₆-cycloalkyl”). Said C₃-C₆-cycloalkyl group is a monocyclichydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

The term “4- to 6-membered heterocycloalkyl” means a monocyclic,saturated heterocycle with 4, 5 or 6 ring atoms in total, which containsone or two identical or different ring heteroatoms from the series N, Oand S, it being possible for said heterocycloalkyl group to be attachedto the rest of the molecule via any one of the carbon atoms or, ifpresent, a nitrogen atom.

Said heterocycloalkyl group, without being limited thereto, can be a4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example;or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl,thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or1,3-thiazolidinyl, for example; or a 6-membered ring, such astetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or1,2-oxazinanyl, for example.

Particularly, “4- to 6-membered heterocycloalkyl” means a 4- to6-membered heterocycloalkyl as defined supra containing one ring oxygenatom and optionally one further ring heteroatom from the series: N, O,S. More particularly, “5- or 6-membered heterocycloalkyl” means amonocyclic, saturated heterocycle with 5 or 6 ring atoms in total,containing one ring oxygen atom.

The term “monocyclic heteroaryl” means a monovalent, aromatic ringhaving 5 or 6 ring atoms (a “5- or 6-membered heteroaryl” group), whichcontains at least one ring heteroatom and optionally one or two furtherring heteroatoms from the series: N, O and/or S, and which is bound viaa ring carbon atom or optionally via a ring nitrogen atom (if allowed byvalency).

Said heteroaryl group can be a 5-membered heteroaryl group, such as, forexample, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as,for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl.

In general, and unless otherwise mentioned, the heteroaryl orheteroarylene groups include all possible isomeric forms thereof, e.g.:tautomers and positional isomers with respect to the point of linkage tothe rest of the molecule. Thus, for some illustrative non-restrictingexamples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl andpyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

Particularly, the heteroaryl group is a pyridinyl group.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of the present invention optionally contain one or moreasymmetric centres, depending upon the location and nature of thevarious substituents desired. It is possible that one or more asymmetriccarbon atoms are present in the (R) or (S) configuration, which canresult in racemic mixtures in the case of a single asymmetric centre,and in diastereomeric mixtures in the case of multiple asymmetriccentres. In certain instances, it is possible that asymmetry also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthe present invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

Preferred isomers are those which produce the more desirable biologicalactivity. These separated, pure or partially purified isomers or racemicmixtures of the compounds of this invention are also included within thescope of the present invention. The purification and the separation ofsuch materials can be accomplished by standard techniques known in theart.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., HPLC columns using a chiral phase), with orwithout conventional derivatisation, optimally chosen to maximise theseparation of the enantiomers. Suitable HPLC columns using a chiralphase are commercially available, such as those manufactured by Deicel,e.g., Chiracel O D and Chiracel O J, for example, among many others,which are all routinely selectable. Enzymatic separations, with orwithout derivatisation, are also useful. The optically active compoundsof the present invention can likewise be obtained by chiral synthesesutilizing optically active starting materials.

In order to distinguish different types of isomers from each otherreference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30,1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. (R)- or (S)-isomers, in any ratio.Isolation of a single stereoisomer, e.g. a single enantiomer or a singlediastereomer, of a compound of the present invention is achieved by anysuitable state of the art method, such as chromatography, especiallychiral chromatography, for example.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also covers useful forms of the compounds of thepresent invention, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, and/orco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example, asstructural element of the crystal lattice of the compounds. It ispossible for the amount of polar solvents, in particular water, to existin a stoichiometric or non-stoichiometric ratio. In the case ofstoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-,di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, arepossible. The present invention includes all such hydrates or solvates.

Further, it is possible for the compounds of the present invention toexist in free form, e.g. as a free base, or as a free acid, or as azwitterion, or to exist in the form of a salt. Said salt may be anysalt, either an organic or inorganic addition salt, particularly anypharmaceutically acceptable organic or inorganic addition salt, which iscustomarily used in pharmacy, or which is used, for example, forisolating or purifying the compounds of the present invention.

The term “pharmaceutically acceptable salt” refers to an inorganic ororganic acid addition salt of a compound of the present invention. Forexample, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, or “mineral acid”, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric,phosphoric, or nitric acid, for example, or with an organic acid, suchas formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic,butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic,itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic,benzenesulfonic, para-toluenesulfonic, methanesulfonic,2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic,adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic,glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, orthiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium, magnesium or strontium salt, or analuminium or a zinc salt, or an ammonium salt derived from ammonia orfrom an organic primary, secondary or tertiary amine having 1 to 20carbon atoms, such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol,diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine,1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine,N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine,glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol,3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with aquarternary ammonium ion having 1 to 20 carbon atoms, such astetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium,tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline orbenzalkonium.

Those skilled in the art will further recognise that it is possible foracid addition salts of the claimed compounds to be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods. Alternatively, alkali and alkaline earthmetal salts of acidic compounds of the present invention are prepared byreacting the compounds of the present invention with the appropriatebase via a variety of known methods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown. Unless specified otherwise, suffixes to chemicalnames or structural formulae relating to salts, such as “hydrochloride”,“trifluoroacetate”, “sodium salt”, or “x HCl”, “x CF₃COOH”, “x Na”, forexample, mean a salt form, the stoichiometry of which salt form notbeing specified.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates, with (if defined) unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

Moreover, the present invention also includes prodrugs of the compoundsaccording to the invention. The term “prodrugs” here designatescompounds which themselves can be biologically active or inactive, butare converted (for example metabolically or hydrolytically) intocompounds according to the invention during their residence time in thebody.

The invention further includes all possible crystallized and polymorphicforms of the inventive compounds, whereby the polymorphs are existingeither as a single polymorph form or are existing as a mixture ofseveral polymorphs in all concentrations.

In accordance with a second embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   4- to 6-membered heterocycloalkyl substituted once with hydroxy        or C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (4- to 6-membered heterocycloalkyl substituted once with        hydroxy)-C₁-C₄-alkyl;-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, halogen or cyano;-   R⁵ represents hydrogen or halogen;-   R⁶ represents hydrogen or halogen;-   R⁷ represents C₁-C₄-alkoxy, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano or —NR⁸R⁹;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R10 represents hydrogen or C₁-C₄-alkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a third embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R¹ represents C₂-C₆-hydroxyalkyl, wherein said C₂-C₆-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with fluoro or chloro, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy, or    -   4- to 6-membered heterocycloalkyl substituted once with hydroxy;-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;-   R³ represents hydrogen or methyl;-   R⁴ represents hydrogen, fluoro or chloro;-   R⁵ represents hydrogen or fluoro;-   R⁶ represents hydrogen or fluoro;-   R⁷ represents methoxy, cyclopropyl or tetrahydrofuranyl;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or methyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a forth embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R¹ represents C₃-C₅-hydroxyalkyl, wherein said C₃-C₅-hydroxyalkyl    groups are optionally substituted one to three times with fluoro, or    -   cyclopentyl substituted once with hydroxy, or    -   tetrahydrothiophenyl substituted once with hydroxy;-   R² represents methyl, difluoromethyl, trifluoromethyl, methoxy or    —NR⁸R⁹;-   R³ represents hydrogen;-   R⁴ represents hydrogen, fluoro or chloro;-   R⁵ represents hydrogen or fluoro;-   R⁶ represents hydrogen or fluoro;-   R⁸ and R⁹ represent methyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   4- to 6-membered heterocycloalkyl substituted once with hydroxy        or C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (4- to 6-membered heterocycloalkyl substituted once with        hydroxy)-C₁-C₄-alkyl;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R¹ represents C₂-C₆-hydroxyalkyl, wherein said C₂-C₆-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with fluoro or chloro, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy, or    -   4- to 6-membered heterocycloalkyl substituted once with hydroxy;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R¹ represents C₃-C₅-hydroxyalkyl, wherein said C₃-C₅-hydroxyalkyl    groups are optionally substituted one to three times with fluoro, or    -   cyclopentyl substituted once with hydroxy, or    -   tetrahydrothiophenyl substituted once with hydroxy;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R¹ represents C₃-C₅-hydroxyalkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy or —NR⁸R⁹;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy or —N(CH₃)₂;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R² represents methyl, difluoromethyl, trifluoromethyl, methoxy or    —N(CH₃)₂;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R³ represents hydrogen, halogen or methyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R³ represents hydrogen or methyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R³ represents hydrogen;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, halogen or cyano;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁴ represents hydrogen, fluoro or chloro;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁵ represents hydrogen or halogen;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁵ represents hydrogen or fluoro;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁶ represents hydrogen or halogen;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁶ represents hydrogen or fluoro;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, 4- to 6-membered    heterocycloalkyl, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano or —NR⁸R⁹;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents C₁-C₄-alkoxy, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano or —NR⁸R⁹;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents methoxy, cyclopropyl or tetrahydrofuranyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents methoxy, cyclopropyl or tetrahydrofuran-3-yl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents methoxy;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents cyclopropyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁷ represents tetrahydrofuran-3-yl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or    -   C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;        their polymorphs, enantiomeres, diastereomeres, racemates,        tautomeres, N-oxides, hydrates and solvates, as well as their        physiological acceptable salts and solvates of these salts, as        well as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or methyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R⁸ and R⁹ represent methyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   R10 represents hydrogen or C₁-C₄-alkyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents N;-   Y represents CR³;-   Z represents CH;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH;-   Y represents N;-   Z represents CH;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In accordance with a further embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

-   X represents CH;-   Y represents N;-   Z represents N;-   R² represents trifluoromethyl;    their polymorphs, enantiomeres, diastereomeres, racemates,    tautomeres, N-oxides, hydrates and solvates, as well as their    physiological acceptable salts and solvates of these salts, as well    as mixtures of the same.

In a particular further embodiment of the first aspect, the presentinvention covers combinations of two or more of the above mentionedembodiments under the heading “further embodiments of the first aspectof the present invention”.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of compounds of general formula (I),supra.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of intermediate compounds of generalformula (VII). The present invention covers the compounds of generalformula (I) which are disclosed in the Example Section of this text,infra.

The compounds according to the invention of general formula (I) can beprepared according to the following scheme 1. The scheme and proceduresdescribed below illustrate synthetic routes to the compounds of generalformula (I) of the invention and are not intended to be limiting. It isclear to the person skilled in the art that the order of transformationsas exemplified in scheme 1 can be modified in various ways. The order oftransformations exemplified in this scheme is therefore not intended tobe limiting. In addition, interconversion of any of the substituentsR¹R², R³, R⁴, R⁵ or R⁶ can be achieved before and/or after theexemplified transformations. These modifications can be such as theintroduction of protecting groups, cleavage of protecting groups,reduction or oxidation of functional groups, halogenation, metallation,metal-catalysed coupling reactions, substitution or other reactionsknown to the person skilled in the art. These transformations includethose which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart. Specific examples are described in the subsequent paragraphs.

Scheme 1 shows a route for the preparation of compounds of generalformula (I) in which R¹, R², R⁴, R⁵, R⁶, X, Y and Z have the meaning asgiven for general formula (I), supra. Ketomalonates represented asintermediates according to formula (III) are in some few instancescommercially available or can be synthezised fromalpha-halo-acetophenones (II) according to procedures known to personsskilled in the art. Related alpha-halo-acetophenones are usuallycommercially available. Conversion of such alpha-halo-acteophenones withmalonic acid esters in the presence of a suitable base in a suitablesolvent results in the formation of non-commercial ketomalonatesaccording to formula (III). R in formula (III), (V) and (VI) representsa suitable alkyl group such as methyl, ethyl, propyl or other homologousgroups. A suitable solvent can be, but should not be restricted to,acetonitrile, DMF, DMA, DMSO of THF, or even mixtures of these or othersolvents. A suitable base could be, but should not be restricted to,potassium carbonate, sodium hydride, cesium carbonate or potassiumhexamethylendisilazane (see e.g.: J. Heterocycl. Chem., 25, (1988), p.1689ﬀ; Med. Chem. Lett., 12, (2002), p. 1955 ﬀ.; J. Med. Chem., 58,(2015), p. 3471 ﬀ.).

Formation of dihydropyridazinones according to formula (V) fromintermediates (III) and suitable aryl-hydrazines (IV), which are in manycases commercially available, can be accomplished by reaction of thesecomponents in a suitable solvent at elevated temperature. R⁴, R⁵, and R⁶in intermediates (IV) are as defined for formula (I), supra. A suitablesolvent could be, but should not be restricted to, ethanol or aceticacid (see e.g.: J. Med. Chem. 19, (1976), p. 787 ﬀ.; Tetrahedron, 65,(2009), p. 4212 ﬀ., J. Med. Chem., 44, (2001), p. 2511 ﬀ.).

Dihydropyridazinones according to formula (V) can be transferred topyridazinones according to formula (VI). This can be accomplished by theuse of a suitable reagents such as copper dichloride at elevatedtemperature (Bioorg. Med. Chem. Lett., 21, (2011), P. 6362 ﬀ.;Synthesis, (2003), p. 436 ﬀ.; J. Med. Chem., 46, (2003), p. 349 ﬀ.).

The resulting pyridazinones according to formula (VI) with an esterfunctional group can be converted by methods known to the person skilledin the art, for example by basic hydrolysis with, for example, aqueousalkali metal hydroxides, or by acidic hydrolysis using, for example,hydrogen chloride in dioxane or trifluoroacetic acid, into thepyridazinone carboxylic acids (VII).

These acids can be converted by coupling with amines of the formula(VIII) in which R¹ is as defined for the general formula (I), supra.Coupling agents and methods for such syntheses of carboxamides fromcarboxylic acids and amines are known to the person skilled in the art.Examples which may be mentioned here include the use of HATU, HBTU,PyBOB or T3P with the addition of a suitable base. The conversion of thecarboxylic acids to their amides is described in general terms inreference books.

Formation of dihydropyridazinones according to formula (IX) fromintermediates (III) and hydrazine, can be accomplished by reaction ofthese components in a suitable solvent at elevated temperature. Asuitable sovent can be, but should not be restricted to, ethanol oracetic acid. R in formula (III), (IX), (X) and (VI) represents asuitable alkyl group such as C₁-C₄ alkyl.

Dihydropyridazinones according to formula (IX) can be transferred topyridazinones according to formula (X). This can be accomplished by theuse of a suitable reagent. A suitable reagent can be, but should not berestricted to, copper dichloride at elevated temperature.

Substituted pyridazinones according to formula (VI) can be prepared byChan-Lam coupling reactions of pyridazinones according to formula (X)using boron dervatives (XI) as boronic acids, boronic acid pinacolates,and mida boronates with suitable solvents at room temperature orelevated temperatures. A suitable solvent can be, but should not berestricted to, acetonitrile, dichloromethane, pyridine or DMF. Asuitable catalyst can be, but should not be restricted to copper (II)acetate. Suitable basic additives can be, but should not be restrictedto, trialkylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

The resulting substituted pyridazinones according to formula (VI) withan ester functional group can be converted by methods known to theperson skilled in the art, for example by basic hydrolysis with, forexample, aqueous alkali metal hydroxides, or by acidic hydrolysis using,for example, hydrogen chloride in dioxane or trifluoroacetic acid, intothe pyridazinone carboxylic acids (VII).

These can be converted by coupling with amines of the formula (VIII) inwhich R¹ is defined as for the general formula (I), supra. Couplingagents and methods for such syntheses of carboxamides from carboxylicacids and amines are known to the person skilled in the art. Exampleswhich may be mentioned here include the use of HATU, HBTU, PyBOB or T3Pwith the addition of a suitable base. The conversion of the carboxylicacids to their amides is described in general terms in reference books.

Compounds of general formula (XII) are commercially available and can bereacted with dialkyl ketomalonate in which R represents C₁-C₄-alkyl.Diethyl ketomalonate as reagent is commercially available. Dialkylketomalonates can be prepared from the corresponding dialkyl malonateswith tosylazide and dioxirane (see e.g.: Synth. Commun. 1994, 24, 695)or bromine and potassium acetate (see e.g.: J. Org. Chem. 1981, 46,2598). The acetophenones of general formula (XII) and the dialkylketomalonates are heated neat at 95-100° C. or with a solvent, e.g.pyridine, under reflux at 120° C. Then, the intermediates of formula(XIII) are reacted with hydrazine hydrate in acetic acid under reflux orhydrazinium dihydrochloride in ethanol under reflux to give theintermediates (X).

Methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate (XIV) [CAS89581-64-6] is commercially available. Conversion of methyl6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate with organoboronderivatives (XV) (boronic acids, boronic acid pinacolates, midaboronates) in the presence of a suitable palladium (0) catalyst, asuitable base and in a suitable solvent at room temperature or elevatedtemperatures leads to the formation of 6-aryl substituted3-oxo-2,3-dihydropyridazine-4-carboxylic acids of formula (XVI).Organoboron derivatives used are commercially available or can besynthesized from organohalides. Methods for such syntheses are known tothe person skilled in the art. A suitable catalyst can be, but shouldnot be restricted to, palladium-phosphine complexes as Pd(PPh₃)₄,PdCl₂(PPh₃)₂, or palladium catalysts which can be prepared in situ fromthe precursors such as Pd(OAc)₂ or Pd₂(dba)₃.CHCl₃, with appropriateamounts of phosphines or palladacycle catalysts as eg. the 2ndgeneration RuPhos precatalyst,chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),RuPhos-Pd-G2. A suitable base can be, but should not be restricted to,potassium phosphate, potassium carbonate, potassium tert.-butylate,cesium carbonate and trialkylamine. A suitable solvent can be, butshould not be restricted to, dioxane, toluene, THF and dimethylformamideor even mixtures of these or other solvents.

The 3-oxo-2,3-dihydropyridazine-4-carboxylic acids (XVI) can beconverted to the amides (XVII) by coupling with amines of the formula(VIII). Coupling agents and methods for such syntheses of carboxamidesfrom carboxylic acids and amines are known to the person skilled in theart. Examples which may be mentioned here include the use of HATU, HBTU,PyBOB or T3P with the addition of a suitable base. The conversion of thecarboxylic acids to their amides is described in general terms inreference books.

Substituted pyridazinones of formula (I) can be prepared from (XVII) byChan-Lam coupling reactions using boronic acid dervatives (XI) (boronicacids, boronic acid pinacolates, mida boronates) in suitable solvents atroom temperature or elevated temperatures. A suitable solvent can be,but should not be restricted to, acetonitrile, dichloromethane, pyridineand DMF. A suitable catalyst can be, but should not be restricted to,copper (II) acetate. Suitable basic additives can be, but should not berestricted to, trialkylamine, 2,2-bipyridine, sodium carbonate or cesiumcarbonate.

6-Chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (XVIII) [CAS50681-26-0] is commercially available and can be converted by couplingwith amines of the formula (VIII) to amides of formula (XIX). Couplingagents and methods for such syntheses of carboxamides from carboxylicacids and amines are known to the person skilled in the art. Exampleswhich may be mentioned here include the use of HATU, H BTU, PyBOB or T3Pwith the addition of a suitable base.

6-Chloro-3-oxo-2,3-dihydropyridazine-4-carboxamides (XIX) can betransformed with organoboron derivatives (XV) (boronic acids, boronicacid pinacolates, mida boronates) in the presence of a suitablepalladium (0) catalyst, a suitable base and in a suitable solvent atroom temperature or elevated temperatures to 6-aryl substituted3-oxo-2,3-dihydropyridazine-4-carboxamides of formula (XVII).Organoboron derivatives used are commercially available or can besynthesized from organohalides. Methods for such syntheses are known tothe person skilled in the art. A suitable catalyst can be, but shouldnot be restricted to palladium-phosphine complexes as Pd(PPh₃)₄,PdCl₂(PPh₃)₂ or palladium catalysts which can be prepared in situ fromthe precursors such as Pd(OAc)₂ or Pd2(dba)₃.CHCl₃, with appropriateamounts of phosphines or palladacycle catalysts as e.g. the 2ndgeneration RuPhos precatalyst,chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),RuPhos-Pd-G2. A suitable base can be, but should not be restricted topotassium phosphate, potassium carbonate, potassium tert.-butylate,cesium carbonate and triehylamine. A suitable solvent can be, but shouldnot be restricted to, dioxane, toluene, THF and dimethylformamide oreven mixtures of these or other solvents.

Substituted pyridazinones according to formula (I) can be prepared byChan-Lam coupling reactions of 6-aryl substituted3-oxo-2,3-dihydropyridazine-4-carboxamides according to formula (XVII)using boronic acid dervatives (XI) (boronic acids, boronic acidpinacolates, mida boronates) with suitable solvents at room temperatureor elevated temperatures. A suitable solvent can be, but should not berestricted to, acetonitrile, dichloromethane, pyridine and DMF. Asuitable catalyst can be, but should not be restricted to copper (II)acetate. Suitable basic additives can be, but should not be restrictedto, trialkylamine, 2,2-bipyridine, sodium carbonate or caesiumcarbonate.

The compounds are either commercially available or can be preparedaccording to procedures available from the public domain, asunderstandable to the person skilled in the art. Specific examples aredescribed in the Experimental Section.

In accordance with a second aspect, the present invention covers methodsof preparing compounds of general formula (I) as defined supra, saidmethods comprising the step of allowing an intermediate compound ofgeneral formula (VII):

-   in which-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, halogen or cyano;-   R⁵ represents hydrogen or halogen;-   R⁶ represents hydrogen or halogen;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R¹⁰ represents hydrogen or C₁-C₄-alkyl;    to react with a compound of general formula (VIII) :

H₂N—R¹   (VIII),

-   in which-   R¹ represents C₂-C₈-hydroxyalkyl, wherein said C₂-C₈-hydroxyalkyl    groups are optionally substituted once with R⁷ and optionally one to    three times with halogen, or    -   C₃-C₆-cycloalkyl substituted once with hydroxy or        C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (C₃-C₆-cycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl, or    -   4- to 6-membered heterocycloalkyl substituted once with hydroxy        or C₁-C₃-hydroxyalkyl and optionally one to three times with        halogen, or    -   (4- to 6-membered heterocycloalkyl substituted once with        hydroxy)-C₁-C₄-alkyl, in which R⁷ is as defined supra.        thereby giving a compound of general formula (I) :

-   in which R¹, R², R⁴, R⁵, R⁶, X, Y and Z are as defined supra.

The present invention covers methods of preparing compounds of thepresent invention of general formula (I), said methods comprising thesteps as described in the Experimental Section herein.

In accordance with a third aspect, the present invention coversintermediate compounds which are useful for the preparation of thecompounds of general formula (I), supra. Particularly, the inventionscovers the intermediate compounds of general formula (VII) :

-   in which-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, halogen or cyano;-   R⁵ represents hydrogen or halogen;-   R⁶ represents hydrogen or halogen;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R¹⁰ represents hydrogen or C₁-C₄-alkyl;

In accordance with a forth aspect, the present invention covers the useof said intermediate compounds for the preparation of a compound ofgeneral formula (I) as defined supra. Particularly, the inventionscovers the use of intermediate compounds of general formula (VII) :

-   in which-   X represents CH or N;-   Y represents CR³ or N;-   Z represents CH or N, wherein    -   if X represents N, Y represents CR³ and Z represents CH, and    -   if X represents CH, Y represents N and Z represents CH, and    -   if Z represents N, Y represents N, X represents CH and R²        represents trifluoromethyl;-   R² represents chloro, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or    —NR⁸R⁹;-   R³ represents hydrogen, halogen or methyl;-   R⁴ represents hydrogen, methyl, fluoromethyl, difluoromethyl,    trifluoromethyl, halogen or cyano;-   R⁵ represents hydrogen or halogen;-   R⁶ represents hydrogen or halogen;-   R⁸ and R⁹ are the same or different and represent, independently    from each other, hydrogen or C₁-C₃-alkyl, or    -   together with the nitrogen atom to which they are attached form        a 4- to 6-membered nitrogen containing heterocyclic ring, said        ring optionally containing one additional heteroatom selected        from O, S, NH, NR^(a) in which R^(a) represents a C₁-C₄-alkyl        group;-   R¹⁰ represents hydrogen or C₁-C₄-alkyl; for the preparation of a    compound of general formula (I) as defined supra.

The present invention covers the intermediate compounds which aredisclosed in the Example Section of this text, infra.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of intermediate compounds of generalformula (VII), supra.

The compounds of general formula (I) of the present invention can beconverted to any salt, preferably pharmaceutically acceptable salts, asdescribed herein, by any method which is known to the person skilled inthe art. Similarly, any salt of a compound of general formula (I) of thepresent invention can be converted into the free compound, by any methodwhich is known to the person skilled in the art.

Compounds of general formula (I) of the present invention demonstrate avaluable pharmacological spectrum of action, which could not have beenpredicted. Compounds of the present invention have surprisingly beenfound to effectively inhibit AHR and it is possible therefore that saidcompounds be used for the treatment or prophylaxis of diseases,preferably cancer or conditions with dysregulated immune responses orother disorders associated with aberrant AHR signaling, in humans andanimals.

Disorders and conditions particularly suitable for treatment with an AHRinhibitor of the present invention are liquid and solid tumours, such ascancers of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukaemias.

Examples of breast cancers include, but are not limited to, triplenegative breast cancer, invasive ductal carcinoma, invasive lobularcarcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to, small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma. Examples of braincancers include, but are not limited to, brain stem and hypophtalmicglioma, cerebellar and cerebral astrocytoma, glioblastoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited to,prostate and testicular cancer.

Tumours of the female reproductive organs include, but are not limitedto, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as wellas sarcoma of the uterus.

Examples of ovarian cancer include, but are not limited to seroustumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa celltumour, Sertoli-Leydig cell tumour and arrhenoblastoma.

Examples of cervical cancer include, but are not limited to squamouscell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cellcarcinoma, neuroendocrine tumour, glassy cell carcinoma andvilloglandular adenocarcinoma.

Tumours of the digestive tract include, but are not limited to, anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers. Examples of esophagealcancer include, but are not limited to esophageal cell carcinomas andadenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma,malignant melanoma, rhabdomyosarcoma and lymphoma.

Examples of gastric cancer include, but are not limited to intestinaltype and diffuse type gastric adenocarcinoma.

Examples of pancreatic cancer include, but are not limited to ductaladenocarcinoma, adenosquamous carcinomas and pancreatic endocrinetumours.

Tumours of the urinary tract include, but are not limited to, bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Examples of kidney cancer include, but are not limited to renal cellcarcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour(reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma,clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms'tumour.

Examples of bladder cancer include, but are not limited to transitionalcell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma andsmall cell carcinoma.

Eye cancers include, but are not limited to, intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to,hepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to, squamous cellcancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal,oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancerand squamous cell.

Lymphomas include, but are not limited to, AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to, sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

The term “treating” or “treatment” as stated throughout this document isused conventionally, for example the management or care of a subject forthe purpose of combating, alleviating, reducing, relieving, improvingthe condition of a disease or disorder, such as a carcinoma.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Generally, the use of chemotherapeutic agents and/or anti-cancer agentsin combination with a compound or pharmaceutical composition of thepresent invention will serve to:

yield better efficacy in reducing the growth of a tumour or eveneliminate the tumour as compared to administration of either agentalone,

provide for the administration of lesser amounts of the administeredchemotherapeutic agents, provide for a chemotherapeutic treatment thatis well tolerated in the patient with fewer deleterious pharmacologicalcomplications than observed with single agent chemotherapies and certainother combined therapies,

provide for treating a broader spectrum of different cancer types inmammals, especially humans,

provide for a higher response rate among treated patients,

provide for a longer survival time among treated patients compared tostandard chemotherapy treatments,

provide a longer time for tumour progression, and/or

yield efficacy and tolerability results at least as good as those of theagents used alone, compared to known instances where other cancer agentcombinations produce antagonistic effects.

In addition, the compounds of general formula (I) of the presentinvention can also be used in combination with radiotherapy and/orsurgical intervention.

In a further embodiment of the present invention, the compounds ofgeneral formula (I) of the present invention may be used to sensitize acell to radiation, i.e. treatment of a cell with a compound of thepresent invention prior to radiation treatment of the cell renders thecell more susceptible to DNA damage and cell death than the cell wouldbe in the absence of any treatment with a compound of the presentinvention. In one aspect, the cell is treated with at least one compoundof general formula (I) of the present invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the presentinvention in combination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of general formula (I) of the present invention prior to thetreatment of the cell to cause or induce cell death. In one aspect,after the cell is treated with one or more compounds of general formula(I) of the present invention, the cell is treated with at least onecompound, or at least one method, or a combination thereof, in order tocause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In other embodiments of the present invention, a cell is killed bytreating the cell with at least one DNA damaging agent, i.e. aftertreating a cell with one or more compounds of general formula (I) of thepresent invention to sensitize the cell to cell death, the cell istreated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g. cis platin), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In other embodiments, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of general formula (I) of thepresent invention is administered to a cell prior to the radiation orother induction of DNA damage in the cell. In another aspect of theinvention, a compound of general formula (I) of the present invention isadministered to a cell concomitantly with the radiation or otherinduction of DNA damage in the cell. In yet another aspect of theinvention, a compound of general formula (I) of the present invention isadministered to a cell immediately after radiation or other induction ofDNA damage in the cell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

The compounds of the present invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutically active ingredients where the combination causes nounacceptable adverse effects. The present invention also covers suchpharmaceutical combinations. For example, the compounds of the presentinvention can be combined with: 131I-chTNT, abarelix, abiraterone,aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib,aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid,alitretinoin, altretamine, amifostine, aminoglutethimide, hexylaminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolethione, anetumab ravtansine, angiotensin II, antithrombin III,aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase,atezolizumab, axitinib, azacitidine, basiliximab, belotecan,bendamustine, besilesomab, belinostat, bevacizumab, bexarotene,bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib,buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel,cabozantinib, calcitonine, calcium folinate, calcium levofolinate,capecitabine, capromab, carbamazepine carboplatin, carboquone,carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin,ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine,cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid,clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin,decitabine, degarelix, denileukin diftitox, denosumab, depreotide,deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron,doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab,edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin,enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa,epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib,esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide,everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine,lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin,levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin,lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol,melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone,methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin,nelarabine, neridronic acid, netupitant/palonosetron, nivolumab,pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab,nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide,ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin,oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel,palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronicacid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase,PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab,pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed,pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide,Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor,plicamycin, poliglusam, polyestradiol phosphate,polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide,ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone,procarbazine, procodazole, propranolol, quinagolide, rabeprazole,racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed,ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab,rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium(153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab,sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib,sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogenelaherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin,teceleukin, technetium (99mTc) nofetumomab merpentan,99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur+gimeracil+oteracil,temoporfin, temozolomide, temsirolimus, teniposide, testosterone,tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa,tioguanine, tocilizumab, topotecan, toremifene, tositumomab,trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine,treosulfan, tretinoin, trifluridine+tipiracil, trilostane, triptorelin,trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex,valatinib , valrubicin, vandetanib, vapreotide, vemurafenib,vinblastine, vincristine, vindesine, vinflunine, vinorelbine,vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres,zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

The compounds of the invention can further be combined with otherreagents targeting the immune system, such as immune checkpointinhibitors. Compositions comprising a PD-1/-L1 axis antagonist and anAHR antagonist and methods of using the same are provided herein. Datapresented herein demonstrate that a combination of AHR inhibition andblockade of the PD-1/-L1 axis reduces the growth of tumor cells in morethan an additive manner. PD-1, along with its ligands PD-L1 and PD-L2,function as negative regulators of T cell activation. AHR suppressesimmune cell function while increasing cancer cell proliferation andmotility. PD-L1 is overexpressed in many cancers and overexpression ofPD-1 often occurs concomitantly in tumor infiltrating T cells. Thusresults in attenuation of T cell activation and evasion of immunesurveillance, which contributes to impaired antitumor immune responses.(Keir M E et al. (2008) Annu. Rev. Immunol. 26:677). Simultaneouslytargeting both the PD-1/-L1 axis and AHR enhances antitumor immuneresponses in more than an additive manner, leading to reduction of tumorgrowth that is unexpected. In some experiments, the resulting effect isgreater than the expected or calculated additive effect of theindividual components given separately. Thus, compositions comprising aPD-1/-L1 axis antagonist and an AHR antagonist are surprisinglyeffective in enhancing an immune response and in the treatment ofcancer.

In addition, the inventive compounds can also be used as a therapeuticin a variety of other disorders wherein AHR is involved such as,cardiovascular and lung diseases.

Accordingly, the compounds according to the invention are suitable forthe treatment and/or prophylaxis in particular of cardiovascular,inflammatory and fibrotic disorders and of renal disorders, inparticular of acute and chronic renal insufficiency, and also of acuteand chronic renal failure.

Accordingly, the compounds according to the invention can be used inmedicaments for the treatment and/or prophylaxis of cardiovascular,inflammatory and fibrotic disorders, renal disorders, in particular ofacute and chronic renal insufficiency, and also of acute and chronicrenal failure.

For the purpose of the present invention the term renal insufficiencycomprises both acute and chronic manifestations of renal insufficiency,and also underlying or related renal disorders such as diabetic andnon-diabetic nephropathies, hypertensive nephropathies, ischaemic renaldisorders, renal hypoperfusion, intradialytic hypotension, obstructiveuropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as,for example, primary glomerulonephritides; minimal changeglomerulonephritis (lipoidnephrosis); membranous glomerulonephritis;focal segmental glomerulosclerosis (FSGS); membrane-proliferativeglomerulonephritis; crescentic glomerulonephritis; mesangioproliferativeglomerulonephritis (IgA nephritis, Berger's disease); post-infectiousglomerulonephritis; secondary glomerulonephritides: diabetes mellitus,lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegenergranulomatosis, Henoch-Schönlein purpura, microscopic polyangiitis,acute glomerulonephritis, pyelonephritis (for example as a result of:urolithiasis, benign prostate hyperplasia, diabetes, malformations,abuse of analgesics, Crohn's disease), glomerulosclerosis,arteriolonecrose of the kidney, tubulointerstitial diseases,nephropathic disorders such as primary and congenital or aquired renaldisorder, Alport syndrome, nephritis, immunological kidney disorderssuch as kidney transplant rejection and immunocomplex-induced renaldisorders, nephropathy induced by toxic substances, nephropathy inducedby contrast agents, diabetic and non-diabetic nephropathy, renal cysts,nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndromewhich can be characterized diagnostically, for example by abnormallyreduced creatinine and/or water excretion, abnormally elevated bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, for example glutamyl synthetase, alteredurine osmolarity or urine volume, elevated microalbuminuria,macroalbuminuria, lesions on glomerulae and arterioles, tubulardilatation, hyperphosphataemia and/or the need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prophylaxis of sequelae of renalinsufficiency, for example pulmonary oedema, heart failure, uremia,anemia, electrolyte disturbances (for example hypercalemia,hyponatremia) and disturbances in bone and carbohydrate metabolism.

The present invention also comprises the use of the compounds accordingto the invention for the treatment and/or prevention of sequelae ofrenal insufficiency, for example pulmonary oedema, heart failure,uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia,hyponatraemia) and disturbances in bone and carbohydrate metabolism.

The compounds according to the invention are further suitable for thetreatment and/or prevention of polycystic kidney disease (PCKD) and ofthe syndrome of inappropriate ADH secretion (SIADH).

Furthermore, the compounds according to the invention are also suitablefor the treatment and/or prophylaxis of metabolic syndrome,hypertension, resistant hypertension, acute and chronic heart failure,coronary heart disease, stable and unstable angina pectoris, peripheraland cardiac vascular disorders, arrhythmias, atrial and ventriculararrhythmias and impaired conduction, for example atrioventricular blocksdegrees I-III (AB block I-III), supraventricular tachyarrhythmia, atrialfibrillation, atrial flutter, ventricular fibrillation, ventricularflutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia,atrial and ventricular extrasystoles, AV-junctional extrasystoles, sicksinus syndrome, syncopes, AV-nodal re-entry tachycardia,Wolff-Parkinson-White syndrome, of acute coronary syndrome (ACS),autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis,aortitis, cardiomyopathies), shock such as cardiogenic shock, septicshock and anaphylactic shock, aneurysms, boxer cardiomyopathy (prematureventricular contraction (PVC)), for treatment and/or prophylaxis ofthromboembolic disorders and ischaemias such as myocardial ischaemia,myocardial infarction, stroke, cardiac hypertrophy, transient andischaemic attacks, preeclampsia, inflammatory cardiovascular disorders,spasms of the coronary arteries and peripheral arteries, oedemaformation, for example pulmonary oedema, cerebral oedema, renal oedemaor oedema caused by heart failure, peripheral circulatory disturbances,reperfusion damage, arterial and venous thromboses, myocardialinsufficiency, endothelial dysfunction, to prevent restenoses, forexample after thrombolysis therapies, percutaneous transluminalangioplasties (PTA), transluminal coronary angioplasties (PTCA), hearttransplants and bypass operations, and also micro- and macrovasculardamage (vasculitis), increased levels of fibrinogen and of low-densitylipoprotein (LDL) and increased concentrations of plasminogen activatorinhibitor 1 (PAI-1), and also for treatment and/or prophylaxis oferectile dysfunction and female sexual dysfunction.

In addition, the compounds according to the invention are also suitablefor treatment and/or prophylaxis of asthmatic disorders, pulmonaryarterial hypertension (PAH) and other forms of pulmonary hypertension(PH) including left-heart disease, HIV, sickle cell anaemia,thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonaryfibrosis-associated pulmonary hypertension, chronic-obstructivepulmonary disease (COPD), acute respiratory distress syndrome (ARDS),acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD),pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysemainduced by cigarette smoke) and cystic fibrosis (CF).

The compounds described in the present invention are also activecompounds for control of central nervous system disorders characterizedby disturbances of the NO/cGMP system. They are suitable in particularfor improving perception, concentration, learning or memory aftercognitive impairments like those occurring in particular in associationwith situations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, Alzheimer'sdisease, Lewy body dementia, dementia with degeneration of the frontallobes including Pick's syndrome, Parkinson's disease, progressivedementia with corticobasal degeneration, amyolateral sclerosis (ALS),Huntington's disease, demyelinization, multiple sclerosis, thalamicdegeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophreniawith dementia or Korsakoff's psychosis. They are also suitable fortreatment and/or prophylaxis of central nervous system disorders such asstates of anxiety, tension and depression, CNS-related sexualdysfunctions and sleep disturbances, and for controlling pathologicaldisturbances of the intake of food, stimulants and addictive substances.

The compounds according to the invention are furthermore also suitablefor controlling cerebral blood flow and thus represent effective agentsfor controlling migraines. They are also suitable for the prophylaxisand control of sequelae of cerebral infarction (cerebral apoplexy) suchas stroke, cerebral ischaemia and craniocerebral trauma. The compoundsaccording to the invention can likewise be used for controlling statesof pain and tinnitus.

The compounds according to the invention are also suitable for treatmentand/or prophylaxis of fibrotic disorders of the internal organs, forexample the lung, the heart, the kidney, the bone marrow and inparticular the liver, and also dermatological fibroses and fibrotic eyedisorders. In the context of the present invention, the term fibroticdisorders includes in particular the following terms: hepatic fibrosis,cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis,nephropathy, glomerulonephritis, interstitial renal fibrosis, fibroticdamage resulting from diabetes, bone marrow fibrosis and similarfibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring(also following surgical procedures), naevi, diabetic retinopathy,proliferative vitroretinopathy and disorders of the connective tissue(for example sarcoidosis). The compounds according to the invention arealso suitable for controlling postoperative scarring, for example as aresult of glaucoma operations.

The compounds according to the invention can also be used cosmeticallyfor ageing and keratinized skin.

Moreover, the compounds according to the invention are suitable fortreatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,glaucoma and gastroparesis.

The present invention further provides for the use of the compoundsaccording to the invention for treatment and/or prophylaxis ofdisorders, especially the disorders mentioned above.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofchronic renal disorders, acute and chronic renal insufficiency,diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders,cardiac insufficiency, angina pectoris, hypertension, pulmonaryhypertension, ischemias, vascular disorders, thromboembolic disorders,arteriosclerosis, sickle cell anemia, erectile dysfunction, benignprostate hyperplasia, dysuria associated with benign prostatehyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.

The present invention further provides a method for treatment and/orprophylaxis of disorders, in particular the disorders mentioned above,using an effective amount of at least one of the compounds according tothe invention.

The present invention further provides a method for the treatment and/orprophylaxis of chronic renal disorders, acute and chronic renalinsufficiency, diabetic, inflammatory or hypertensive nephropathies,fibrotic disorders, cardiac insufficiency, angina pectoris,hypertension, pulmonary hypertension, ischemias, vascular disorders,thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectiledysfunction, benign prostate hyperplasia, dysuria associated with benignprostate hyperplasia, Huntington, dementia, Alzheimer andCreutzfeld-Jakob.

In another embodiment, the inventive compounds can also be used to treator to prevent uterine fibroids (uterine leiomyoma or uterine myoma) inwomen.

Uterine fibroids are benign tumors of the myometrium, the smooth musclelayer of the uterus. Uterine fibroids grow slowly during a women's life,and their growth is dependent on the female sexual hormones estradioland progesterone [Kawaguchi K et al. Immunohistochemical analysis ofoestrogen receptors, progesterone receptors and Ki-67 in leiomyoma andmyometrium during the menstrual cycle and pregnancy Virchows Arch APathol Anat Histopathol. 1991;419(4):309-15,], therefore the highestprevalence of uterine fibroids with approx. 70% and >80% in white andafro-american women, respectively, is found from 35 years of age onwardsto menopause, when they shrink due to reduced hormone levels [Baird D Det al. High cumulative incidence of uterine leiomyoma in black and whitewomen: Ultrasound evidence Am J Obstet Gynecol. 2003 Jan;188(1):100-7.].Approx 30% and 45% of white and afro-american women, respectively, doshow clinically relevant symptoms due to their fibroids, which are heavymenstrual bleeding and pain, which is related to the menstrual cycle[David M et al. Myoma-associated pain frequency and intensity: aretrospective evaluation of 1548 myoma patients. Eur J Obstet GynecolReprod Biol. 2016 Apr;199:137-40]. Heavy menstrual bleeding in thisrespect is defined by a blood loss of more than 80 mL in a menstrualbleeding period [Fraser I S et al. The FIGO Recommendations onTerminologies and Definitions for Normal and Abnormal Uterine Bleeding,Semin Reprod Med 2011; 29(5): 383-390]. Submucosal position of theuterine fibroids, e.g. those located directly below the endometrium,seems to have an even more severe effect on uterine bleeding, which mayresult in anemia in affected women [Yang J H et al. Impact of submucousmyoma on the severity of anemia. Fertil Steril. 2011 Apr;95(5):1769-72].Furthermore, uterine fibroids, due to their symptoms, do severly affectthe quality of life of affected women [Downes E et al. The burden ofuterine fibroids in five European countries. Eur J Obstet Gynecol ReprodBiol. 2010 Sep;152(1):96-102].

So far, it is not understood how uterine fibroids do cause heavymenstrual bleeding. Disregulated genes in uterine fibroids, incomparison to normal myometrium, can give a hint to understand theunderlying mechanisms. In published and internal studies, we found TDO2,Tryptophan 2,3-dioxygenase, being highly upregulated [Tsibris JC et al.Insights from gene arrays on the development and growth regulation ofuterine leiomyomata. Fertil Steril. 2002 Jul;78(1):1 14-21.]. TDO2metabolizes the substrate L-Tryptophan to L-Kynurenine, which can befurther metabolized to kynurenic acid. Both, L-Kynurenine and Kynurenicacid are physiological ligands and activators for the arylhydrocarbonreceptor AHR [Opitz CA et al. An endogenous tumour-promoting ligand ofthe human aryl hydrocarbon receptor Nature. 2011 Oct5;478(7368):197-203].

L-Kynurenine controls at least two physiological processes which aredysregulated in uterine fibroids. L-Kynurenine, synthesized by anupregulation of IDO (Indoleamine-2,3-dyoxygenase) or TDO2, and actingvia the AHR receptor, suppresses the immune system and thus preventsimmune cells from recognizing and clearing the tumor cells [Munn DHBlocking IDO activity to enhance anti-tumor immunity. Front Biosci(Elite Ed). 2012 Jan 1;4:734-45]. Furthermore, an upregulation ofL-Kynurenine leads to a vasodilation of vessels, and thus can directlyincrease blood loss and bleeding [Wang Y et al. Kynurenine is anendothelium-derived relaxing factor produced during inflammation NatureMedicine 16,279-285 (2010)].

In summary, the upregulation of L-Kynurenine through activation of itsphysiological receptor AHR seems to support uterine fibroid growth bylocal suppression of the immune system, and might cause heavy menstrualbleeding by vasodilation of endometrial vessels in proximity to thetumor.

Therefore, a systemic or local application of compounds from the presentinvention inhibiting activation of the AHR and thus blocking the effectof uterine fibroid derived L-Kynurenine presents a new and validtreatment option for uterine fibroids.

Compounds of the present invention can be utilized to inhibit, block,reduce or decrease AHR activation by exogenous and/or endogenous ligandsfor the reduction of tumour growth and the modulation of dysregulatedimmune responses e.g. to block immunosuppression and increase immunecell activation and infiltration in the context of cancer and cancerimmunotherapy; This method comprises administering to a mammal in needthereof, including a human, an amount of a compound of this invention,or a pharmaceutically acceptable salt, isomer, polymorph, metabolite,hydrate, solvate or ester thereof; which is effective to treat thedisorder.

The present invention also provides methods of treating a variety ofother disorders wherein AHR is involved such as, but not limited to,inflammation, vaccination for infection & cancer, viral infections,obesity and diet-induced obesity, adiposity, metabolic disorders,hepatic steatosis and uterine fibroids.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as used in the present text is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as liquid and solid tumours.

In accordance with a further aspect, the present invention coverscompounds of general formula (I), as described supra, or stereoisomers,tautomers, N-oxides, hydrates, solvates, and salts thereof, particularlypharmaceutically acceptable salts thereof, or mixtures of same, for usein the treatment or prophylaxis of diseases, in particular cancer orconditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their activity as AHR inhibitors.

In accordance with a further aspect, the present invention covers theuse of compounds of general formula (I), as described supra, orstereoisomers, tautomers, N-oxides, hydrates, solvates, and saltsthereof, particularly pharmaceutically acceptable salts thereof, ormixtures of same, for the treatment or prophylaxis of diseases, inparticular cancer or conditions with dysregulated immune responses orother disorders associated with aberrant AHR signaling, particularlyliquid and solid tumours.

In accordance with a further aspect, the present invention covers theuse of a compound of formula (I), described supra, or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for the prophylaxis or treatment of diseases, in particular canceror conditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling, particularly liquid and solidtumours.

In accordance with a further aspect, the present invention covers theuse of compounds of general formula (I), as described supra, orstereoisomers, tautomers, N-oxides, hydrates, solvates, and saltsthereof, particularly pharmaceutically acceptable salts thereof, ormixtures of same, in a method of treatment or prophylaxis of diseases,in particular cancer or conditions with dysregulated immune responses orother disorders associated with aberrant AHR signaling, particularlyliquid and solid tumours.

In accordance with a further aspect, the present invention covers use ofa compound of general formula (I), as described supra, or stereoisomers,tautomers, N-oxides, hydrates, solvates, and salts thereof, particularlypharmaceutically acceptable salts thereof, or mixtures of same, for thepreparation of a pharmaceutical composition, preferably a medicament,for the prophylaxis or treatment of diseases, in particular cancer orconditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling, particularly liquid and solidtumours.

In accordance with a further aspect, the present invention covers amethod of treatment or prophylaxis of diseases, in particular cancer orconditions with dysregulated immune responses or other disordersassociated with aberrant AHR signaling, particularly liquid and solidtumours, using an effective amount of a compound of general formula (I),as described supra, or stereoisomers, tautomers, N-oxides, hydrates,solvates, and salts thereof, particularly pharmaceutically acceptablesalts thereof, or mixtures of same.

In accordance with a further aspect, the present invention coverspharmaceutical compositions, in particular a medicament, comprising acompound of general formula (I), as described supra, or a stereoisomer,a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof,particularly a pharmaceutically acceptable salt, or a mixture of same,and one or more excipients), in particular one or more pharmaceuticallyacceptable excipient(s). Conventional procedures for preparing suchpharmaceutical compositions in appropriate dosage forms can be utilized.

The present invention furthermore covers pharmaceutical compositions, inparticular medicaments, which comprise at least one compound accordingto the invention, conventionally together with one or morepharmaceutically suitable excipients, and to their use for the abovementioned purposes.

It is possible for the compounds according to the invention to havesystemic and/or local activity. For this purpose, they can beadministered in a suitable manner, such as, for example, via the oral,parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal,vaginal, dermal, transdermal, conjunctival, otic route or as an implantor stent.

For these administration routes, it is possible for the compoundsaccording to the invention to be administered in suitable administrationforms.

For oral administration, it is possible to formulate the compoundsaccording to the invention to dosage forms known in the art that deliverthe compounds of the invention rapidly and/or in a modified manner, suchas, for example, tablets (uncoated or coated tablets, for example withenteric or controlled release coatings that dissolve with a delay or areinsoluble), orally-disintegrating tablets, films/wafers,films/lyophylisates, capsules (for example hard or soft gelatinecapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions. It is possible to incorporate thecompounds according to the invention in crystalline and/or amorphisedand/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of anabsorption step (for example intravenous, intraarterial, intracardial,intraspinal or intralumbal) or with inclusion of absorption (for exampleintramuscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal). Administration forms which are suitable for parenteraladministration are, inter alia, preparations for injection and infusionin the form of solutions, suspensions, emulsions, lyophylisates orsterile powders.

Examples which are suitable for other administration routes arepharmaceutical forms for inhalation [inter alia powder inhalers,nebulizers], nasal drops, nasal solutions, nasal sprays;tablets/films/wafers/capsules for lingual, sublingual or buccaladministration; suppositories; eye drops, eye ointments, eye baths,ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, eartampons; vaginal capsules, aqueous suspensions (lotions, mixturaeagitandae), lipophilic suspensions, emulsions, ointments, creams,transdermal therapeutic systems (such as, for example, patches), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into thestated administration forms. This can be effected in a manner known perse by mixing with pharmaceutically suitable excipients. Pharmaceuticallysuitable excipients include, inter alia,

fillers and carriers (for example cellulose, microcrystalline cellulose(such as, for example,) Avicel®), lactose, mannitol, starch, calciumphosphate (such as, for example, Di-Cafos®)), ointment bases (forexample petroleum jelly, paraffins, triglycerides, waxes, wool wax, woolwax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

bases for suppositories (for example polyethylene glycols, cacao butter,hard fat), solvents (for example water, ethanol, isopropanol, glycerol,propylene glycol, medium chain-length triglycerides fatty oils, liquidpolyethylene glycols, paraffins),

surfactants, emulsifiers, dispersants or wetters (for example sodiumdodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, forexample, Lanette®), sorbitan fatty acid esters (such as, for example,Span®), polyoxyethylene sorbitan fatty acid esters (such as, forexample, Tween®), polyoxyethylene fatty acid glycerides (such as, forexample, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylenefatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as,for example, Pluronic®),

buffers, acids and bases (for example phosphates, carbonates, citricacid, acetic acid, hydrochloric acid, sodium hydroxide solution,ammonium carbonate, trometamol, triethanolamine),

isotonicity agents (for example glucose, sodium chloride),

adsorbents (for example highly-disperse silicas),

viscosity-increasing agents, gel formers, thickeners and/or binders (forexample polyvinylpyrrolidone, methylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose,carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids(such as, for example, Carbopol®); alginates, gelatine),

disintegrants (for example modified starch,carboxymethylcellulose-sodium, sodium starch glycolate (such as, forexample, Explotab®), cross-linked polyvinylpyrrolidone,croscarmellose-sodium (such as, for example, AcDiSol®)),

flow regulators, lubricants, glidants and mould release agents (forexample magnesium stearate, stearic acid, talc, highly-disperse silicas(such as, for example, Aerosil®)),

coating materials (for example sugar, shellac) and film formers forfilms or diffusion membranes which dissolve rapidly or in a modifiedmanner (for example polyvinylpyrrolidones (such as, for example,Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose,hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulosephthalate, cellulose acetate, cellulose acetate phthalate,polyacrylates, polymethacrylates such as, for example, Eudragit®)),

capsule materials (for example gelatine, hydroxypropylmethylcellulose),

synthetic polymers (for example polylactides, polyglycolides,polyacrylates, polymethacrylates (such as, for example, Eudragit®),polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinylalcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycolsand their copolymers and blockcopolymers),

plasticizers (for example polyethylene glycols, propylene glycol,glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

penetration enhancers,

stabilisers (for example antioxidants such as, for example, ascorbicacid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole,butylhydroxytoluene, propyl gallate),

preservatives (for example parabens, sorbic acid, thiomersal,benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

colourants (for example inorganic pigments such as, for example, ironoxides, titanium dioxide),

flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceuticalcomposition which comprise at least one compound according to theinvention, conventionally together with one or more pharmaceuticallysuitable excipient(s), and to their use according to the presentinvention.

In accordance with another aspect, the present invention coverspharmaceutical combinations, in particular medicaments, comprising atleast one compound of general formula (I) of the present invention andat least one or more further active ingredients, in particular for thetreatment and/or prophylaxis of cancer or conditions with dysregulatedimmune responses or other disorders associated with aberrant AHRsignalinggeneric name disorders, particularly liquid and solid tumours.

The term “combination” in the present invention is used as known topersons skilled in the art, it being possible for said combination to bea fixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein, forexample, a first active ingredient, such as one or more compounds ofgeneral formula (I) of the present invention, and a further activeingredient are present together in one unit dosage or in one singleentity. One example of a “fixed combination” is a pharmaceuticalcomposition wherein a first active ingredient and a further activeingredient are present in admixture for simultaneous administration,such as in a formulation. Another example of a “fixed combination” is apharmaceutical combination wherein a first active ingredient and afurther active ingredient are present in one unit without being inadmixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein a first active ingredient and a further activeingredient are present in more than one unit. One example of a non-fixedcombination or kit-of-parts is a combination wherein the first activeingredient and the further active ingredient are present separately. Itis possible for the components of the non-fixed combination orkit-of-parts to be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of cancer or conditions with dysregulatedimmune responses or other disorders associated with aberrant AHRsignaling, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown active ingredients or medicaments that are used to treat theseconditions, the effective dosage of the compounds of the presentinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient to be administered inthe treatment of one of these conditions can vary widely according tosuch considerations as the particular compound and dosage unit employed,the mode of administration, the period of treatment, the age and sex ofthe patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, it is possible for “drug holidays”, in which a patient is notdosed with a drug for a certain period of time, to be beneficial to theoverall balance between pharmacological effect and tolerability. It ispossible for a unit dosage to contain from about 0.5 mg to about 1500 mgof active ingredient, and can be administered one or more times per dayor less than once a day. The average daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. The average daily rectaldosage regimen will preferably be from 0.01 to 200 mg/kg of total bodyweight. The average daily vaginal dosage regimen will preferably be from0.01 to 200 mg/kg of total body weight. The average daily topical dosageregimen will preferably be from 0.1 to 200 mg administered between oneto four times daily. The transdermal concentration will preferably bethat required to maintain a daily dose of from 0.01 to 200 mg/kg. Theaverage daily inhalation dosage regimen will preferably be from 0.01 to100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Experimental Section

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered. The multiplicities are statedaccording to the signal form which appears in the spectrum,NMR-spectroscopic effects of a higher order were not taken intoconsideration. Multiplicity of the NMR signals: s=singlet, d=doublet,t=triplet, q=quartet, qi=quintet, b=broad signal, m=multiplet. NMRsignals: shift in ppm. Combinations of multiplicity could be e.g.dd=doublet from doublet.

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

Table 1 lists the abbreviations used in this paragraph and in theExamples section as far as they are not explained within the text body.Other abbreviations have their meanings customary per se to the skilledperson.

TABLE 1 Abbreviations ACN acetonitrile AcOH acetic acid BPR BackPressure Regulator CDCl₃ deuterochloroform DAD diode array detector DEAdiethylamine DMF N,N-dimethylformamide DMSO-d6 deuterated dimethylsulfoxide DMSO dimethyl sulfoxide Expl. example HATU(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HBTU O-benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HPLC high-pressure liquid chromatography KAkynurenic acid LCMS liquid chromatography coupled with mass spectrometryLPS lipopolysaccharide μL microliter mL milliliter min minute(s) MTBEmethyl tert-butyl ether p pressure PBMC peripheral blood mononuclearcells PyBOB (benzotriazol-1-yl)oxytripyrrolidinophosphoniumhexafluorophosphate RP-HPLC reverse-phase high-pressure liquidchromatography Rt retention time rt room temperature sat. saturated T3P2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide THFtetrahydrofurane TFA trifluoroacetic acid TLC thin layer chromatographyTNFa tumour necrosis factor alpha μM micromolar UPLC Ultra highperformance chromatography

The various aspects of the invention described in this application areillustrated by the following examples which are not meant to limit theinvention in any way.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Experimental Section—General Part

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera Four®) and eluents such as gradients of hexane/ethylacetate or dichloromethane/methanol. In some cases, the compounds may bepurified by preparative HPLC using for example a Waters autopurifierequipped with a diode array detector and/or on-line electrosprayionization mass spectrometer in combination with a suitable prepackedreverse phase column and eluents such as gradients of water andacetonitrile which may contain additives such as trifluoroacetic acid,formic acid or aqueous ammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the person skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

UPLC Methods

Method 1 : Instrument: Waters Acquity UPLC-MS SQD 3001; column: AcquityUPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.1 vol% formic acid(99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2 μL; DAD scan:210-400 nm; ELSD.

Method 2: Instrument: Waters Acquity UPLC-MS SQD 3001; column: AcquityUPLC BEH C18 1.7 μm, 50×2.1 mm; eluent A: water+0.2 vol% aqueous ammonia(32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2 μL; DAD scan:210-400 nm; ELSD.

Preparativ HPLC Methods

Instrument: pump: Labomatic HD-3000, head HDK 280, lowpressure gradientmodule ND-B1000; manual injection valve: Rheodyne 3725i038; detector:Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column:Chromatorex RP C-18 10 μm, 125×30 mm; eluent; gradient; UV-Detection.

Eluent acidic: solvent A: water+0.1 vol% formic acid (99%), solvent B:acetonitrile; flow 150 mL/min.

Method A: 0.00-0.50 min 1% B, 0.50-6.00 min 1-25% B, 6.00-6.10 min25-100% B, 6.10-8.00 min 100% B

Method B: 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B, 6.00-6.10 min50-100% B, 6.10-8.00 min 100% B

Method C: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B, 6.00-6.10 min55-100% B, 6.10-8.00 min 100% B

Method D: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B, 6.00-6.10 min70-100% B, 6.10-8.00 min 100% B

EXPERIMENTAL SECTION—INTERMEDIATES Intermediate 1 Diethyl2-hydroxy-2-[2-oxo-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]propanedioate

Into a 100-mL round-bottom flask, was placed1-[6-(trifluoromethyl)-3-pyridyl]ethanone (10 g, 52.87 mmol) and1,3-diethyl 2-oxopropanedioate (15.65 g, 89.9 mmol). The resultingsolution was stirred for 24 h at 130° C. followed by the addition ofmore 1,3-diethyl 2-oxopropanedioate (13.81 g, 79.30 mmol) and heatingfor another 13 h at 130° C. The resulting mixture was cooled down to rtand poured into pentane. The precipitate was filtered off, washed withpentane and water yielding 22.6 g (crude) of diethyl2-hydroxy-2-[2-oxo-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]propanedioatewhich was used without further purification.

Intermediate 2 Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate

To a solution of diethyl2-hydroxy-2-[2-oxo-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]propanedioate(22.6 g, 62.2 mmol) in ethanol (255 mL) was added hydrazinehydrochloride (7.2 g, 68.5 mmol). The resulting solution was stirred for24 h at 80° C. The reaction was then quenched by the addition of water.The resulting precipitate was filtered off and dried in vacuum to give13.26 g (68%) of ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.32 (t, 3H), 4.33 (q, 2H), 8.01-8.06(m, 1H), 8.47-8.51 (m, 1H), 8.52-8.57 (m, 1H), 9.23-9.26 (m, 1H), 13.92(s, 1H).

Intermediate 3 Ethyl2-(3,5-difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate

Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate (150mg, 0.48 mmol) was dissolved in acetonitrile (4 mL) followed by theaddition of molecular sieves (4 Å, powder, 0.133 g),(3,5-difluorophenyl)boronic acid (113.4 mg, 0.72 mmol), triethylamine(0.13 mL, 0.96 mmol), pyridine (0.08 mL, 0.96 mmol) and anhydrous copperdiacetate (174 mg, 0.96 mmol). The reaction mixture was stirred for 3 hat 80° C., filtered through silica gel, concentrated and used withoutfurther purification.

LC-MS (method 1): R_(t)=1.35 min; MS (ESlpos): m/z=426.3 [M+H]⁺

Intermediate 42-(3,5-Difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylicacid

Ethyl2-(3,5-difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate(91.6 mg, 0.22 mmol) was dissolved in tetrahydrofurane (2 mL) followedby the addition of 0.32 mL of aqueous 2N sodium hydroxide solution. Thereaction mixture was stirred over night at rt. Water was added to thereaction mixture and the pH was adjusted to pH 3 with 1M hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 62mg (85%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=7.41-7.50 (m, 1H), 7.55-7.63 (m, 2H),8.05 (d, 1H), 8.59-8.63 (m, 1H), 8.63-8.69 (m, 1H), 9.35 (d, 1H).

Intermediate 5 Ethyl2-(3-chloro-5-fluoro-phenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate

Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate (150mg, 0.48 mmol) was dissolved in acetonitrile (4 mL) followed by theaddition of molecular sieves (4 Å, powder, 0.133 g),(3-chloro-5-fluoro-phenyl)boronic acid (125.2 mg, 0.72 mmol),triethylamine (0.13 mL, 0.96 mmol), pyridine (0.08 mL, 0.96 mmol) andanhydrous copper diacetate (174 mg, 0.96 mmol). The reaction mixture wasstirred for 3 h at 80° C., filtered through silica gel, concentrated andused without further purification.

LC-MS (method 1): R_(t)=1.41 min; MS (ESlpos): m/z=442.3 [M+H]⁺

Intermediate 62-(3-Chloro-5-fluoro-phenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylicacid

Ethyl2-(3-chloro-5-fluoro-phenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate(107 mg, 0.24 mmol) was dissolved in tetrahydrofurane (2 mL) followed bythe addition of 0.36 mL of aqueous 2N sodium hydroxide solution. Thereaction mixture was stirred over night at rt. Water was added to thereaction mixture and the pH was adjusted to pH 3 with 1M hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 74mg (74%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=7.61-7.67 (m, 1H), 7.69-7.74 (m, 1H),7.75-7.79 (m, 1H), 8.03-8.09 (m, 1H), 8.60-8.62 (m, 1H), 8.63-8.68 (m,1H), 9.33-9.38 (m, 1H).

Intermediate 72-(3,4-difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate

Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate (150mg, 0.48 mmol) was dissolved in acetonitrile (4 mL) followed by theaddition of molecular sieves (4 Å, powder, 0.133 g),(3,4-difluorophenyl)boronic acid (113.4 mg, 0.72 mmol), triethylamine(0.13 mL, 0.96 mmol), pyridine (0.08 mL, 0.96 mmol) and anhydrous copperdiacetate (174 mg, 0.96 mmol). The reaction mixture was stirred for 3 hat 80° C., filtered through silica gel, concentrated and used withoutfurther purification.

LC-MS (method 1): R_(t)=1.33 min; MS (ESlpos): m/z=426.3 [M+H]⁺

Intermediate 82-(3,4-Difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylicacid

Ethyl2-(3,4-difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate(125 mg, 0.44 mmol) was dissolved in tetrahydrofurane (2 mL) followed bythe addition of 0.36 mL of aqueous 2N sodium hydroxide solution. Thereaction mixture was stirred over night at rt. Water was added to thereaction mixture and the pH was adjusted to pH 3 with 1M hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 66mg (56%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=7.60-7.72 (m, 2H), 7.89-7.97 (m, 1H),8.02-8.07 (m, 1H), 8.59-8.66 (m, 2H), 9.31-9.36 (m, 1H).

Intermediate 9 Ethyl2-(3-chlorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate

Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate (500mg, 1.6 mmol) was dissolved in acetonitrile (4 mL) followed by theaddition of molecular sieves (4 Å, powder, 0.133 g),(3-chlorophenyl)boronic acid (374.4 mg, 2.4 mmol), triethylamine (0.44mL, 3.2 mmol), pyridine (0.26 mL, 3.2 mmol) and anhydrous copperdiacetate (580 mg, 3.2 mmol). The reaction mixture was stirred for 2 hat 80° C., filtered through silica gel, concentrated and used withoutfurther purification.

LC-MS (method 1): R_(t)=1.37 min; MS (ESlpos): m/z=425.3 [M+H]⁺

Intermediate 102-(3-Chlorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylicacid

Ethyl2-(3-chlorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate(626 mg, 1.47 mmol) was dissolved in tetrahydrofurane (11 mL) followedby the addition of 2.2 mL of aqueous 2N sodium hydroxide solution. Thereaction mixture was stirred over night at rt. Water was added to thereaction mixture and the pH was adjusted to pH 2 with 1M hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 498mg (85%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=7.57-7.64 (m, 2H), 7.67-7.73 (m, 1H),7.84-7.87 (m, 1H), 8.05 (d, 1H), 8.61-8.66 (m, 2H), 9.32-9.35 (m, 1H).

Intermediate 11 Ethyl3-oxo-2-phenyl-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate

Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate (500mg, 1.6 mmol) was dissolved in acetonitrile (4 mL) followed by theaddition of molecular sieves (4 Å, powder, 0.133 g), phenylboronic acid(292 mg, 2.4 mmol), triethylamine (0.44 mL, 3.2 mmol), pyridine (0.26mL, 3.2 mmol) and anhydrous copper diacetate (580 mg, 3.2 mmol). Thereaction mixture was stirred for 2 h at 80° C., filtered through silicagel, concentrated and used without further purification.

LC-MS (method 1): R_(t)=1.27 min; MS (ESlpos): m/z=390.6 [M+H]⁺

Intermediate 123-Oxo-2-phenyl-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylicacid

Ethyl3-oxo-2-phenyl-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate(627 mg, 1.47 mmol) was dissolved in tetrahydrofurane (11 mL) followedby the addition of 2.4 mL of aqueous 2N sodium hydroxide solution. Thereaction mixture was stirred over night at rt. Water was added to thereaction mixture and the pH was adjusted to pH 2 with 1M hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 416mg (72%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=7.48-7.61 (m, 3H), 7.67-7.73 (m, 2H),8.04 (d, 1H), 8.62 (dd, 1H), 8.65 (s, 1H), 9.27-9.37 (m, 1H).

Intermediate 13 Ethyl2-(3-fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate

Ethyl6-oxo-3-[6-(trifluoromethyl)-3-pyridyl]-1H-pyridazine-5-carboxylate (500mg, 1.6 mmol) was dissolved in acetonitrile (4 mL) followed by theaddition of molecular sieves (4 Å, powder, 0.133 g),(3-fluorophenyl)boronic acid (335 mg, 2.4 mmol), triethylamine (0.44 mL,3.2 mmol), pyridine (0.26 mL, 3.2 mmol) and anhydrous copper diacetate(580 mg, 3.2 mmol). The reaction mixture was stirred for 3 h at 80° C.,filtered through silica gel, concentrated and used without furtherpurification.

LC-MS (method 1): R_(t)=1.30 min; MS (ESIpos): m/z=408.7 [M+H]⁺

Intermediate 142-(3-Fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylicacid

Ethyl2-(3-fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylate(480 mg, 1.47 mmol) was dissolved in tetrahydrofurane (9 mL) followed bythe addition of 1.8 mL of aqueous 2N sodium hydroxide solution. Thereaction mixture was stirred over night at rt. Water was added to thereaction mixture and the pH was adjusted to pH 3 with 1M hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 350mg (78%) of the title compound.

LC-MS (method 1): R_(t)=1.19 min; MS (ESlpos): m/z=380.5 [M+H]⁺

Intermediate 156-Chloro-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide

A solution of 7.5 g (43 mmol) of3-chloro-6-oxo-1H-pyridazine-5-carboxylic acid, 4.28 g (55 mmol) of(25)-2-amino-1-propanol, 32.7 g (86 mmol) of HATU, 22.5 mL ofethyldiisopropylamine and 262 mg of 4-dimethylaminopyridine in 150 mL ofDMF was stirred over night at rt. The reaction mixture was quenched withwater and extracted five times with dichloromethane. The combinedorganic phases were evaporated whereby a precipitate was formed. Theprecipitate was filtered off and dried to afford 2.21 g (22%) of thetitle compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.13 (d, 3H), 3.38-3.47 (m, 2H),3.80-4.04 (m, 1H), 4.92 (t, 1H), 7.99 (s, 1H), 9.32-9.55 (m, 1H),13.83-14.08 (m, 1H).

Intermediate 166-Chloro-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide

6-Chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (2.5 g, 14.3mmol) was dissolved in anhydrous dimethylformamide (50 mL).(3R)-3-amino-2-methyl-butan-2-ol hydrochloride (2.73 g, 18.6 mmol),N-ethyl-N-diisopropylamine (11.2 mL, 64.5 mmol), and propane phosphonicacid anhydride (T3P, 12.5 mL, 50% in DMF, 21.5 mmol) were successivelyadded. After stirring over night at rt the reaction mixture was stirredat 50° C. for another 2 h. The reaction mixture was quenched with waterand extracted three times with ethyl acetate. The combined organicphases were washed with saturated aqueous ammonium hydrochloridesolution, dried over sodium sulfate, filtered and concentrated undervacuum to yield 2.19 g (59%) of the title compound.

¹H NMR (500 MHz, DMSO-d₆) δ ppm=0.99-1.15 (m, 9H), 3.79-3.93 (m, 1H),4.55-4.75 (m, 1H), 7.92-8.03 (m, 1H), 9.54-9.71 (m, 1H), 13.29-14.32 (m,1H).

Intermediate 17 Diethylhydroxy{2-oxo-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}malonate

Into a 50-mL round-bottom flask, was placed1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanone (1 g, 5 mmol) and1,3-diethyl 2-oxopropanedioate (2.6 g, 15 mmol). The resulting solutionwas stirred for 24 h at 130° C. The resulting mixture was cooled down tort and poured into pentane. As no precipitate was formed, the reactionmixture was evaporated and purified by column chromatography (silicagel, hexane/ethyl acetate, gradient) to yield 1.33 g (73%) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.11-1.27 (m, 6H), 3.84 (s, 2H),4.06-4.27 (m, 4H), 7.34 (s, 1H), 9.50 (s, 2H).

Intermediate 18 Ethyl3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxylate

To a solution of diethylhydroxy{2-oxo-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}malonate (1.33g, 3.65 mmol) in ethanol (15 mL) was added hydrazine hydrochloride (0.42g, 4.0 mmol). The resulting solution was stirred for 8 h at 80° C. Thereaction was then quenched by the addition of water. The resultingprecipitate was filtered off and dried in vacuum to give 581 mg (51%) ofethyl3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxylate.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.32 (t, 3H), 4.33 (q, 2H), 8.53 (s,1H), 9.50 (s, 2H).

Intermediate 192-(3-Fluorophenyl)-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxylicacid

Ethyl3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxylate(550 mg, 1.75 mmol) was dissolved in acetonitrile (15 mL) followed bythe addition of molecular sieves (4 Å, powder, 0.133 g),2-(3-fluorophenyl)-4,4,5-trimethyl-1,3,2-dioxaborolane (583 mg, 2.6mmol), triethylamine (0.49 mL, 3.2 mmol), pyridine (0.26 mL, 3.5 mmol)and anhydrous copper diacetate (635 mg, 3.5 mmol). The reaction mixturewas stirred for 3 h at 80° C., cooled down and treated with 2N sodiumhydroxide solution (1.75 mL, 3.5 mmol) over night at rt. Then the pH wasadjusted to pH 3 with 1M hydrochloric acid. After addition of water themixture was extracted with ethyl acetate. The combined organic phaseswere dried and concentrated to dryness in vacuum to yield 520 mg (78%,crude) of the title compound.

LC-MS (method 2): R_(t)=0.67 min; MS (ESlpos): m/z=381.3 [M+H]⁺

Intermediate 20 Diethyl2-hydroxy-2-[2-(5-methyl-2-pyridyl)-2-oxo-ethyl]propanedioate

Into a 50-mL round-bottom flask, was placed1-(5-methylpyridin-2-yl)ethanone (500 mg, 3.7 mmol) and 1,3-diethyl2-oxopropanedioate (1.1 g, 6.3 mmol). The resulting solution was stirredfor 5 h at 130° C. followed by the addition of 1,3-diethyl2-oxopropanedioate (1.1 g, 6.3 mmol) two times and overall stirring at130° C. for 30 h. The resulting mixture was cooled down to rt and pouredinto ethyl acetate and water. The phases were separated and the aqueousphase was extracted three times with ethyl acetate. The combined organicphases were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by column chromatography (silicagel, hexane/ethyl acetate, gradient) to yield 1.68 g (quant. crude) ofthe title compound.

LC-MS (method 1): R_(t)=1.04 min; MS (ESlpos): m/z=310.6 [M+H]⁺

Intermediate 21 Ethyl6-(5-methylpyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

To a solution of diethyl2-hydroxy-2-[2-(5-methyl-2-pyridyl)-2-oxo-ethyl]propanedioate (1.68 g,3.7 mmol) in ethanol (15 mL) was added hydrazine hydrochloride (0.42 g,4.0 mmol). The resulting solution was stirred for 8 h at 80° C. Thereaction was then quenched by the addition of water and the mixture wasextracted three times with ethyl acetate. The combined organic phaseswere washed with brine, dried and concentrated in vacuum. The residuewas purified by RP-HPLC (method C) to yield 199 mg (20%) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.30 (t, 3H), 2.36 (s, 3H), 4.31 (q,2H), 7.77 (dt, 1H), 7.97 (d, 1H), 8.43-8.55 (m, 1H), 8.63 (s, 1H), 13.68(s, 1H).

Intermediate 222-(3-Fluorophenyl)-6-(5-methylpyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylicacid

Ethyl 6-(5-methylpyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(199 mg, 0.68 mmol) was dissolved in acetonitrile (7 mL) followed by theaddition of molecular sieves (4 Å, powder, 214 mg),2-(3-fluorophenyl)-4,4,5-trimethyl-1,3,2-dioxaborolane (256 mg, 1.15mmol), triethylamine (0.21 mL, 1.5 mmol), pyridine (0.12 mL, 1.5 mmol)and anhydrous copper diacetate (279 mg, 1.5 mmol). The reaction mixturewas stirred for 3 h at 80° C., cooled down and treated with 2N sodiumhydroxide solution (0.77 mL, 1.5 mmol) over night at rt. Then the pH wasadjusted to pH 3 with 1M hydrochloric acid. After addition of water themixture was extracted with ethyl acetate. The combined organic phaseswere dried and concentrated to dryness in vacuum to yield 55 mg (22%,crude) of the title compound.

LC-MS (method 1): R_(t)=1.19 min; MS (ESlpos): m/z=326.3 [M+H]⁺

Intermediate 236-[6-(Dimethylamino)pyridin-3-yl]-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide

A solution of6-chloro-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide(250 mg, 0.96 mmol) and 2-(dimethylamino)pyridine-5-boronic acid hydrate(230 mg, 1.25 mmol) in 7 mL of dimethylformamide was treated withtripotassium phosphate (5.7 mL of a 0.5M solution in water) and secondgeneration RuPhos Pd precatalyst (CAS No. [1375325-68-0]; 74.7 mg),heated to 75° C. and stirred for 2 h. The reaction mixture was filteredand purified by RP-HPLC (method A) to yield 206 mg (62%) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.10-1.18 (m, 9H), 3.08 (s, 6H),3.88-3.96 (m, 1H), 4.59-4.73 (m, 1H), 6.70-6.74 (m, 1H), 7.97-8.00 (m,1H), 8.46 (s, 1H), 8.58 (d, 1H), 9.76-9.82 (m, 1H).

Intermediate 24N-[(2R)-3-Hydroxy-3-methylbutan-2-yl]-6-(6-methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

A solution of6-chloro-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide(250 mg, 0.96 mmol) and 6-methoxy-3-pyridyl)boronic acid (199 mg, 1.25mmol) in 7 mL of dimethylformamide was treated with tripotassiumphosphate (5.7 mL of a 0.5M solution in water) and second generationRuPhos Pd precatalyst (CAS No. [1375325-68-0]; 74.7 mg), heated to 75°C. and stirred for 2 h. The reaction mixture was filtered and purifiedby RP-HPLC (method B) to yield 174 mg (54%) of the title compound.

LC-MS (method 1): R_(t)=0.83 min; MS (ESlpos): m/z=333.3 [M+H]⁺

Intermediate 256-(6-Methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

A solution of ethyl 6-chloro-3-hydroxypyridazine-4-carboxylate (500 mg,2.47 mmol) and (6-methoxy-3-pyridyl)boronic (491 mg, 3.2 mmol) acid in20 mL of dioxane was treated with tri-potassium phosphate (14.8 mL of a0.5M solution in water) and second generation RuPhos Pd precatalyst (CASNo. [1375325-68-0]; 383 mg), heated to 75° C. and stirred for 30 min.The reaction mixture cooled down and was treated with 2N sodiumhydroxide solution (4.9 mL, 4.9 mmol) over night at rt. Water was addedto the reaction mixture and the pH was adjusted to pH 3 with 1Mhydrochloric acid. The precipitate was filtered off and dried in vacuumto yield 464 mg (76%) of the title compound.

LC-MS (method 1): R_(t)=0.71 min; MS (ESlpos): m/z=248.2 [M+H]⁺

Intermediate 26N-[(1S)-2-Hydroxy-1-methyl-ethyl]-3-(6-methoxy-3-pyridyl)-6-oxo-1H-pyridazine-5-carboxamide

A solution of6-(6-methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid(464 mg, 1.87 mmol), (25)-2-amino-1-propanol (282 mg, 3.75 mmol), HATU(1.42 g, 3.75 mmol), ethyldiisopropylamine (1.3 mL, 7.5 mmol) and4-dimethylaminopyridine (11 mg, 0.09 mmol) in 24 mL of DMF was stirredover night at rt. The reaction mixture was concentrated and quenchedwith water. The precipitate was filtered off and the filtrate wasconcentrated and purified by RP-HPLC (method A) to afford 795 mg (70%)of the title compound.

LC-MS (method 1): R_(t)=0.75 min; MS (ESlpos): m/z=305.2 [M+H]⁺

Intermediate 27 5-Bromo-2-(difluoromethyl)pyridine

Into a 2000-mL 4-necked round-bottom flask, was placed a solution of5-bromopyridine-2-carbaldehyde (30 g, 161.29 mmol, 1.00 equiv) indichloromethane (800 mL). This was followed by the addition of DAST(diethylaminosulfur trifluoride) (40 g, 1.08 mol, 6.69 equiv) dropwisewith stirring at 0° C. The resulting solution was stirred for 12 hoursat room temperature. The reaction was then quenched by the addition ofwater. The pH value of the solution was adjusted to 8 with sodiumcarbonate (2 mol/L). The resulting solution was extracted with 3×500 mLof dichloromethane and the organic layers were combined. The resultingmixture was washed with 1×300 mL of water. The resulting mixture waswashed with 1×300 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 18 g (54%) of 5-bromo-2-(difluoromethyl)pyridine as yellowoil.

Intermediate 28 1[6-(Difluoromethyl)pyridin-3-yl]ethanone

Into a 500-mL 4-necked round-bottom flask, was placed a solution of5-bromo-2-(difluoromethyl)pyridine (18 g, 86.54 mmol, 1.00 equiv) indioxane (180 mL), tributyl(1-ethoxyethenyl)stannane (35 g, 96.91 mmol,1.12 equiv), tetrakis(triphenylphosphane) palladium (3 g, 2.60 mmol,0.03 equiv). The resulting solution was stirred for 2 hat 100° C. Thereaction mixture was cooled with a water bath. The reaction was thenquenched by the addition of 250 mL of (2N) HCl. The pH value of thesolution was adjusted to 8 with sodium carbonate (2 mol/L). Theresulting solution was extracted with 3×500 mL of ethyl acetate and theorganic layers were combined. The resulting mixture was washed with1×200 mL of water. The resulting mixture was washed with 1×200 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 10 g(68%) of 1-[6-(difluoromethyl)pyridin-3-yl]ethan-1-one as yellow oil.

Intermediate 29 Diethyl{2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}(hydroxy)malonate

Into a 100-mL round-bottom flask, was placed1-[6-(difluoromethyl)pyridin-3-yl]ethan-1-one (10 g, 58.43 mmol, 1.00equiv) and 1,3-diethyl 2-oxopropanedioate (15 g, 86.13 mmol, 1.47equiv).

The resulting solution was stirred for 24 h at 130° C. The resultingmixture was concentrated under vacuum. This resulted in 24 g (crude) of1,3-diethyl2-[2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl]-2-hydroxypropanedioateas red oil which was used without further purification.

Intermediate 30 Ethyl6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylate

Into a 500-mL round-bottom flask, was placed a solution of 1,3-diethyl2-[2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl]-2-hydroxypropanedioate(24 g, 69.51 mmol, 1.00 equiv) in ethanol (200 mL) and hydrazine (15mL). The resulting solution was stirred for 12 h at 80° C. The reactionwas then quenched by the addition of water. The resulting solution wasextracted with 3×300 mL of ethyl acetate and the organic layers werecombined. The resulting mixture was washed with 1×100 mL of water. Theresulting mixture was washed with 1×100 mL of brine. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (2:1). This resulted in 2.8 g (14%) of ethyl6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylateas a yellow solid.

H-NMR (300 MHz, DMSO-d₆, ppm) δ=13.84 (s, 1H), 9.17 (s, 1H), 8.48-8.44(m, 2H), 7.84-7.82 (m, 1H), 7.03 (t, 1H), 4.35 (q, 2H), 1.33 (t, 3H).

Intermediate 313-[6-(Difluoromethyl)-3-pyridyl]-6-oxo-1H-pyridazine-5-carboxylic acid

Ethyl6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylate(165 mg, 0.055 mmol) was dissolved in 2 mL of dimethylformamide andtreated with 2N sodium hydroxide solution (0.08 mL, 0.15 mmol) overnight at rt. Water was added and the precipitate was filtered off anddried to yield 147 mg (quant, crude) of the title compound.

LC-MS (method 1): R_(t)=0.68 min; MS (ESlpos): m/z=268.1 [M+H]⁺

Intermediate 323-[6-(Difluoromethyl)-3-pyridyl]-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]-6-oxo-1H-pyridazine-5-carboxamide

To a solution of3-[6-(difluoromethyl)-3-pyridyl]-6-oxo-1H-pyridazine-5-carboxylic acid(147 mg, 0.55 mmol) in anhydrous dimethylformamide (2.6 mL) was added(3R)-3-amino-2-methyl-butan-2-ol hydrochloride (115 mg, 0.83 mmol),diisopropylethylamine (0.43 mL, 2.48 mmol), and propane phosphonic acidanhydride (T3P, 526 mg, 50% in DMF, 0.83 mmol). After stirring overnight at rt the reaction mixture was quenched with water and extractedthree times with ethyl acetate. The combined organic phases were washedwith saturated aqueous ammonium hydrochloride solution and brine anddried over sodium sulfate, filtered and concentrated in vacuum to yield100 mg (52%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.09-1.17 (m, 9H), 3.85-3.97 (m, 1H),4.66 (s, 1H), 6.87-7.22 (m, 1H), 7.80-7.86 (m, 1H), 8.47-8.52 (m, 1H),8.64 (s, 1H), 9.19 (d, 1H), 9.67-9.72 (m, 1H).

Intermediate 33 Dimethyl{2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}malonate

To a solution of 2-bromo-1-[6-(difluoromethyl)-3-pyridyl]ethanone (5 g,20 mmol) in 140 mL of acetone was added dropwise at rt dimethyl malonate(5.28 g, 40 mmol) and potassium carbonate (4.1 g, 30 mmol). The reactionmixture was stirred at rt over night followed by the addition of water.Acetone was removed in vacuo and the remaining aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatography(silica gel, dichloromethane/methanol gradient) to yield 1.06 (18%) ofthe title compound.

LC-MS (method 1): R_(t)=0.95 min; MS (ESlpos): m/z=302.3 [M+H]⁺

Intermediate 34 Methyl6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

Dimethyl {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}malonate (424mg, 1.4 mmol) and sodium acetate (520 mg, 6.34 mmol) were dissolved inacetic acid (14 mL). Then, 3-fluorophenyl hydrazine hydrochloride (236mg, 1.4 mmol) was added portion wise. After stirring for 1 h at rt and 2h at 80° C. additional 3-fluorophenyl hydrazine hydrochloride (118 mg,0.7 mmol) was added. After stirring for 6 h at 80° C. the reactionmixture was cooled down and concentrated on a rotary evaporator underreduced pressure. Ethyl acetate and water were added to dissolve theresidue. Concentrated aqueous sodium hydrogen carbonate solution wasadded, the phases were separated, and the aqueous layer was extractedthree times with ethyl acetate. The combined organic layers were washedtwice with water, dried over sodium sulfate, and concentrated. Theresidue was purified by flash chromatography (silica gel, hexane/ethylacetate, gradient) to afford 142 mg (27%) of the title product.

1H NMR (400 MHz, DMSO-d₆) δ ppm=3.44-3.60 (m, 2H), 3.72 (s, 3H),4.11-4.17 (m, 1H), 6.88-7.22 (m, 2H), 7.39-7.54 (m, 3H), 7.76-7.83 (m,1H), 8.42 (dd, 1H), 9.09-9.14 (m, 1H).

Intermediate 35 Methyl6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

Methyl 6-[6-(difluoromethyl)pyrid in-3-yl]-2-(3-fluorophenyl)-3-oxo-2 ,3,4,5-tetrahydropyridazine-4-carboxylate (142 mg, 0.37 mmol) wasdissolved in acetonitrile (5 mL). Copper dichloride (152 mg, 1.13 mmol)was added. It was stirred for 3 h at 90° C. It was cooled down andconcentrated on a rotary evaporator. Water was added, the remainingsolid was filtered by suction, washed five times with water, and driedunder vacuum at 50° C. to yield 106 mg (75%) of the title compound whichwas used without further purification in the next step.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=3.89 (s, 3H), 6.90-7.20 (m, 1H),7.34-7.40 (m, 1H), 7.55-7.67 (m, 3H), 7.81-7.85 (m, 1H), 8.50-8.55 (m,1H), 8.61-8.63 (m, 1H), 9.23-9.25 (m, 1H).

Intermediate 366-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylicacid

A mixture of methyl6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(106 mg, 0.28 mmol) and 0.35 mL of 2N aqueous sodium hydroxide solutionin 1.5 mL of tetrahydrofurane was stirred at rt for 24 hours. Thereaction mixture was diluted with water and the pH was adjusted to 3with 1M hydrochloric acid and the precipitate was filtered off, washedwith water and dried in vacuo to yield 95 mg (quant.) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=6.89-7.20 (m, 1H), 7.33-7.41 (m, 1H),7.56-7.68 (m, 3H), 7.81-7.85 (m, 1H), 8.52-8.59 (m, 2H), 9.23-9.28 (m,1H).

Intermediate 376-(6-Methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

A solution of ethyl 6-chloro-3-hydroxypyridazine-4-carboxylate (430 mg,2.1 mmol) and 2-methylpyridine-5-boronic acid pinacol ester (605 mg,2.76 mmol) in 10 mL of dioxane was treated with tripotassium phosphate(12.7 mL of a 0.5M solution in water) and second generation RuPhos Pdprecatalyst (CAS No. [1375325-68-0]; 329 mg), heated to 100° C. andstirred for 3 h. The reaction mixture was allowed to cool down and theprecipitate formed was filtered off and dried in vacuum to yield 490 mg(quant.) of the title compound.

Intermediate 38N-[(2S)-1-Hydroxypropan-2-yl]-6-(6-methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

A solution of6-(6-methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid(250 mg, 0.97 mmol), (2S)-2-amino-1-propanol (146.2 mg, 1.95 mmol),propane phosphonic acid anhydride (T3P, 1.7 mL, 50% in ethyl acetate,2.9 mmol) and ethyldiisopropylamine (0.76 mL, 4.4 mmol) in 5 mL of DMSOwas stirred over night at rt. The reaction mixture was purified byRP-HPLC (method A) to afford 11 mg (4%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.16 (d, 3H), 2.53 (s, 3H), 3.43-3.49(m, 2H), 3.97-4.08 (m, 1H), 7.39 (d, 1H), 8.15-8.20 (m, 1H), 8.52-8.56(m, 1H), 8.93-8.97 (m, 1H), 9.56-9.63 (m, 1H).

Intermediate 39 Diethyl[2-(5-chloropyridin-2-yl)-2-oxoethyl](hydroxy)malonate

1-(5-Chloropyridin-2-yl)ethanone (850 mg, 5.46 mmol) and diethylketomalonate (1.9 g, 10.92 mmol) were mixed and stirred at 130° C. for24 h. After cooling to rt, the mixture was taken up in ethyl acetate andwater. The phases were separated and the aqueous phase was extractedthree times with ethyl acetate. The combined organic phases were washedwith brine, filtered (MN 617 WA filter paper) and concentrated. Thecrude product was purified by flash chromatography (silica gel,hexane/ethyl acetate, gradient) to afford 1.04 g (58%) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.17 (t, 6H), 3.84 (s, 2H), 4.16 (q,4H), 6.44 (s, 1H), 7.94-7.98 (m, 1H), 8.13-8.17 (m, 1H), 8.80-8.82 (m,1H).

Intermediat 40 Ethyl6-(5-chloropyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

Diethyl [2-(5-chloropyridin-2-yl)-2-oxoethyl](hydroxy)malonate (1.0 g,3.03 mmol) and hydrazine dihydrochlorid (0.51 g, 4.8 mmol) weredissolved in ethanol (13 mL) and stirred at reflux for 6 h. Afteraddition of water a precipitate formed and was filtered off, washed withwater and dried in vacuum to yield 0.65 g (77%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.30 (t, 3H), 4.31 (q, 2H), 8.07 (d,2H), 8.60 (s, 1H), 8.74 (t, 1H), 13.80 (s, 1H).

Intermediat 416-(5-Chloropyridin-2-yl)-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylicacid

Ethyl 6-(5-chloropyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(150 mg, 0.54 mmol) was dissolved in acetonitrile (5 mL) followed by theaddition of molecular sieves (4 Å, powder, 150 mg),2-(3-fluorophenyl)-4,4,5-trimethyl-1,3,2-dioxaborolane (113 mg, 0.80mmol), triethylamine (0.15 mL, 1.07 mmol), pyridine (0.087 mL, 1.07mmol) and anhydrous copper diacetate (195 mg, 1.07 mmol). The reactionmixture was stirred for 3 h at 80° C., cooled down and treated with 2Nsodium hydroxide solution (1.8 mL, 3.6 mmol) over night at rt. Then thepH was adjusted to pH 3 with 1M hydrochloric acid. A precipitate formed,was filtered off and dried in vacuum to yield 590 mg (95%, crude) of thetitle compound.

LC-MS (method 1): R_(t)=1.26 min; MS (ESlpos): m/z=346.2 [M+H]⁺

Intermediate 42 Diethylhydroxy{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}malonate

1-[5-(Trifluoromethyl)pyridin-2-yl]ethanone (3.8 g, 20.1 mmol) anddiethyl ketomalonate (7.0 g, 40.2 mmol) were mixed and stirred at 130°C. for 24 h. After cooling to rt, the mixture was taken up in ethylacetate and water. The phases were separated and the aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere washed with brine, filtered (MN 617 WA filter paper) andconcentrated. The crude product was purified by flash chromatography(silica gel, hexane/ethyl acetate, gradient) to afford 4.64 g (64%) ofthe title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.18 (t, 6H), 3.91 (q, 2H), 4.17 (q,4H), 6.50 (s, 1H), 8.12 (d, 1H), 8.42-8.47 (m, 1H), 9.17 (dd, 1H).

Intermediat 43 Ethyl3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylate

Diethyl hydroxy{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}malonate(4.6 g, 12.66 mmol) and hydrazine dihydrochlorid (1.79, 17.1 mmol) weredissolved in ethanol (52 mL) and stirred at reflux for 9 h. Afteraddition of water a precipitate formed and was filtered off, washed withwater and dried in vacuum to yield 3.19 g (81%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (t, 3H), 4.32 (q, 2H), 8.24-8.29(m, 1H), 8.35 (dd, 1H), 8.67 (s, 1H), 9.07-9.11 (m, 1H), 13.94 (s, 1H).

Intermediat 44 Ethyl2-(3-fluorophenyl)-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylate

Ethyl3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylate(1.5 g, 4.79 mmol) was dissolved in acetonitrile (42 mL) followed by theaddition of molecular sieves (4 Å, powder, 1.35 g),2-(3-fluorophenyl)-4,4,5-trimethyl-1,3,2-dioxaborolane (1.59 g, 7.2mmol), triethylamine (1.33 mL, 9.6 mmol), pyridine (0.775 mL, 9.6 mmol)and anhydrous copper diacetate (1.74 g, 9.6 mmol). The reaction mixturewas stirred for 3 h at 80° C., cooled down and treated with water. Thenthe pH was adjusted to pH 3 with 1M hydrochloric acid followed by theaddition of ethyl acetate. The phases were separated and the aqueousphase was extracted three times with ethyl acetate. The combined organicphases were washed with brine, filtered (MN 617 WA filter paper) andconcentrated to yield 1.95 g (quant., crude) of the title compound.

LC-MS (method 1): R_(t)=1.42 min; MS (ESlpos): m/z=408.3 [M+H]⁺

Intermediat 452-(3-Fluorophenyl)-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylicacid

Ethyl2-(3-fluorophenyl)-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylate(1.95 g, 4.79 mmol) was solved in THF (25 mL) and treated with 2N sodiumhydroxide solution (9.2 mL, 18.4 mmol) over night at rt. Then the pH wasadjusted to pH 3 with 1M hydrochloric acid. A precipitate formed, wasfiltered off, washed with water and dried in vacuum to yield 1.05 g(58%, crude) of the title compound.

LC-MS (method 1): R_(t)=1.22 min; MS (ESlpos): m/z=380.3 [M+H]⁺

Intermediate 463-Oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylicacid

3.0 g of a crude mixture containing an unknown amount of ethyl3-oxo-6-[5-(trifluoromethyl)-pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylatewas dissolved in tetrahydrofurane (50 mL) followed by the addition of9.2 mL (18.4 mmol) of aqueous 2N sodium hydroxide solution. The reactionmixture was stirred overnight at rt. Water was added to the reactionmixture and the pH was adjusted to pH 3 with 1M aqueous hydrochloricacid. The precipitate was filtered off and dried in vacuum to yield 1.05g of a crude mixture containing the title compound.

LC-MS (method 1): R_(t)=1.04 min; MS (ESlpos): m/z=286.1 [M+H]⁺

Intermediate 47N-[(2S)-1-Hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide

1.051 g of a crude mixture containing an unknown amount of3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylicacid and 312 mg (4.15 mmol) of alaninol were dissolved in 16 mL of DMFand treated with HATU (2.1 g, 5.54 mmol), N,N-diisopropylethylamine(1.07 g, 8.3 mmol) and 4-dimethylaminopyridine (16.9 mg, 0.14 mmol). Thereaction mixture was stirred overnight and taken up in water and ethylacetate. The phases were separated and the organic phase was washed withbrine, filtered (MN 617 WA filter paper) and concentrated. The crudeproduct was purified by flash chromatography (silica gel, hexane/ethylacetate, gradient) to afford 383 mg of the title compound.

LC-MS (method 1): R_(t)=0.93 min; MS (ESlpos): m/z=343.5 [M+H]

EXPERIMENTAL SECTION-EXAMPLES

The following examples describe the embodyment of the instant invention,not restricting the invention to these examples only.

Example 12-(3,5-Difluorophenyl)-N-[(25)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide

2-(3,5-Difluorophenyl)-3-oxo-6-[6-(trifluoromethyl)-3-pyridyl]pyridazine-4-carboxylicacid (62 mg, 0.156 mmol) was dissolved in dimethylformamide (1.5 mL) andtreated with (S)-(+)-2-amino-1-propanol (L-Alaninol, 24 mg, 0.31 mmol),N-ethyl-N-diisopropylamine (0.11 mL, 0.62 mmol) and propane phosphonicacid anhydride (T3P, 1.5 eq., 50% in DMF, 149 mg, 0.23 mmol). Thereaction mixture was stirred over night at rt and then purified by HPLC(method D) to yield 24.5 mg (35%) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm=1.17 (d, 3H), 3.40-3.51 (m, 2H),3.99-4.09 (m, 1H), 4.93-4.98 (m, 1H), 7.45-7.53 (m, 1H), 7.56-7.64 (m,2H), 8.03-8.08 (m, 1H), 8.65-8.70 (m, 1H), 8.78-8.81 (m, 1H), 9.30-9.35(m, 1H), 9.35-9.38 (m, 1H)

The following examples were prepared from the starting materials statedin the table using the following procedure. Enantiomers were separatedfrom their racemate by chiral HPLC using the column and solventconditions stated.

Carboxylic acid (1 eq.) was dissolved in anhydrous dimethylformamide.Amine (1-2 eq.), N-ethyl-N-diisopropylamine (4 eq.) and propanephosphonic acid anhydride (T3P, 1.5 eq., 50% in DMF) were successivelyadded. After stirring over night at rt the reaction mixture was purifieddirectly by HPLC or quenched with water and extracted three times withethyl acetate. The combined organic phases were washed with saturatedaqueous ammonium hydrochloride solution, dried over sodium sulfate,filtered and concentrated under vacuum to yield the crude titlecompound. In general the crude products were purified by RP-HPLC(methods A-D depending on polarity). It is also possible to apply thereaction mixture immediately to RP-H PLC.

TABLE 2 Examples 2-17, 24-26 Example structure IUPAC name Startingmaterials analytics 2

2-(3-Chloro-5- fluorophenyl)-N- [(2S)-1- hydroxypropan-2-yl]-3-oxo-6-[6- (trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine-4-carboxamide 2-(3-Chloro-5- fluoro-phenyl)-3- oxo-6-[6-(trifluoromethyl)-3- pyridyl]pyridazine- 4-carboxylic acid;(S)-(+)-2-Amino-1- propanol (L- Alaninol) ¹H NMR (400 MHz, DMSO- d₆) δppm = 1.17 (d, 3 H), 3.41-3.51 (m, 2 H), 3.99- 4.10 (m, 1 H), 4.93-4.98(m, 1 H), 7.70 (ddt, 2 H), 7.78 (td, 1 H), 8.03-8.07 (m, 1 H), 8.67 (dd,1 H), 8.79 (s, 1 H), 9.30- 9.34 (m, 1 H), 9.35-9.39 (m, 1 H) 3

2-(3,4- Difluorophenyl)- N-[(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3,4-Difluoro- phenyl)-3-oxo-6- [6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; (S)-(+)-2-Amino-1- propanol (L-Alaninol) ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.17 (d, 3 H), 3.40-3.50(m, 2 H), 3.99- 4.09 (m, 1 H), 4.95 (t, 1 H), 7.60-7.72 (m, 2 H), 7.90-7.97 (m, 1 H), 8.02-8.07 (m, 1 H), 8.65 (dd, 1 H), 8.79 (s, 1 H),9.32-9.40 (m, 1 H) 4

2-(3- Chlorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Chlorophenyl)-3- oxo-6-[6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; (S)-(+)-2-Amino-1- propanol (L-Alaninol) ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.17 (d, 3 H), 3.41-3.50(m, 2 H), 3.99- 4.10 (m, 1 H), 4.95 (t, 1 H), 7.60-7.64 (m, 2 H), 7.68-7.73 (m, 1 H), 7.85-7.88 (m, 1 H), 8.02- 8.06 (m, 1 H), 8.62-8.67 (m, 1H), 8.79 (s, 1 H), 9.33-9.35 (m, 1 H), 9.36- 9.41 (m, 1 H) 5

N-[(2S)-1- Hydroxypropan-2- yl]-3-oxo-2- phenyl-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide 3-Oxo-2-phenyl-6-[6- (trifluoromethyl)-3- pyridyl]pyridazine- 4-carboxylic acid;(S)-(+)-2-Amino-1- propanol (L- Alaninol) ¹H NMR (400 MHz, DMSO- d₆) δppm = 1.17 (d, 3 H), 3.40-3.50 (m, 2 H), 4.00- 4.09 (m, 1 H), 4.92-4.96(m, 1 H), 7.49- 7.61 (m, 3 H), 7.66-7.72 (m, 2 H), 8.02- 8.06 (m, 1 H),8.61-8.65 (m, 1 H), 8.78- 8.81 (m, 1 H), 9.31-9.34 (m, 1 H), 9.43- 9.48(m, 1 H) 6

2-(3- Fluorophenyl)-N- [(1S,2S)-2- hydroxycyclo- pentyl]-3- oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; (1S,2S)-2- Aminocyclopen- tanolhydrochloride ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.40-1.56 (m, 2 H),1.58- 1.77 (m, 2 H), 1.77-1.88 (m, 1 H), 2.04- 2.14 (m, 1 H), 3.91-4.06(m, 2 H), 4.90- 5.00 (m, 1 H), 7.37-7.43 (m, 1 H), 7.56- 7.69 (m, 3 H),8.02-8.06 (m, 1 H), 8.63- 8.67 (m, 1 H), 8.77-8.79 (m, 1 H), 9.26- 9.30(m, 1 H), 9.34-9.36 (m, 1 H) 7

2-(3- Fluorophenyl)-N- [(2R)-3-hydroxy- 3-methylbutan-2- yl]-3-oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; (3R)-3-Amino-2- methyl-butan-2-olhydrochloride ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.10 (s, 3 H), 1.14 (d,3 H), 1.16 (s, 3 H), 3.87-3.96 (m, 1 H), 4.66 (s, 1 H), 7.36-7.44 (m, 1H), 7.56- 7.70 (m, 3 H), 8.04 (d, 1 H), 8.62-8.67 (m, 1 H), 8.77- 8.81(m, 1 H), 9.32-9.36 (m, 1 H), 9.47- 9.52 (m, 1 H) 8

2-(3- Fluorophenyl)-N- [(1S,2R)-2- hydroxycyclo- pentyl]-3- oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; cis-(1R,2S)-2- Aminocyclopen-tanol hydrochloride ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.47-1.66 (m, 3H), 1.70- 1.89 (m, 2 H), 1.92-2.04 (m, 1 H), 4.00- 4.12 (m, 2 H),5.04-5.08 (m, 1 H), 7.37- 7.44 (m, 1 H), 7.56-7.68 (m, 3 H), 8.04 (d, 1H), 8.62-8.68 (m, 1 H), 8.79- 8.82 (m, 1 H), 9.34 (d, 1 H), 9.64-9.69(m, 1 H) 9

2-(3- Fluorophenyl)-N- [(2S)-3-hydroxy- 3-methylbutan-2- yl]-3-oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; (3S)-3-Amino-2- methyl-butan-2-olhydrochloride ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.10 (s, 3 H), 1.13 (d,3 H), 1.16 (s, 3 H), 3.88-3.97 (m, 1 H), 4.64- 4.68 (m, 1 H), 7.37-7.44(m, 1 H), 7.57- 7.69 (m, 3 H), 8.02-8.07 (m, 1 H), 8.65 (dd, 1 H), 8.79-8.82 (m, 1 H), 9.34 (d, 1 H), 9.49 (d, 1 H) 10

2-(3- Fluorophenyl)-N- (2-hydroxy-2- methylpropyl)-3- oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[6- (trifluoromethyl)-3-pyridyl]pyridazine- 4-carboxylic acid; 1-Amino-2-methyl- propan-2-ol ¹HNMR (400 MHz, DMSO- d₆) δ ppm = 1.13 (s, 6 H), 3.31 (s, 1 H), 4.68 (s, 1H), 7.37-7.44 (m, 1 H), 7.57- 7.70 (m, 3 H), 8.02-8.07 (m, 1 H), 8.63-8.68 (m, 1 H), 8.79-8.82 (m, 1 H), 9.33- 9.37 (m, 1 H), 9.47-9.53 (m, 1H) 11

2-(3- Fluorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[2-(trifluoromethyl) pyrimidin-5-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[2- (trifluoromethyl) pyrimidin-5-yl]pyridazine-4- carboxylic acid; (S)-(+)-2-Amino-1- propanol (L-Alaninol) ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.17 (d, 3 H), 3.42-3.50(m, 2 H), 3.99- 4.10 (m, 1 H), 4.96 (t, 1 H), 7.36-7.44 (m, 1 H), 7.58-7.65 (m, 2 H), 7.66-7.71 (m, 1 H), 8.86 (s, 1 H), 9.34-9.39 (m, 1 H),9.62 (s, 2 H) 12

2-(3- Fluorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-6-(5-methylpyridin-2- yl)-3-oxo-2,3- dihydropyridazine- 4-carboxamide 2-(3-Fluorophenyl)-6- (5-methyl-2- pyridyl)-3-oxo- pyridazine-4- carboxylicacid; (S)-(+)-2-Amino-1- propanol (L- Alaninol) ¹H NMR (400 MHz, DMSO-d₆) δ ppm = 1.15 (d, 3 H), 2.37 (s, 3 H), 3.42-3.48 (m, 2 H), 3.99- 4.08(m, 1 H), 4.92-4.96 (m, 1 H), 7.36- 7.42 (m, 1 H), 7.54-7.58 (m, 1 H),7.60- 7.66 (m, 2 H), 7.75-7.80 (m, 1 H), 8.00- 8.04 (m, 1 H), 8.57-8.61(m, 1 H), 9.05- 9.07 (m, 1 H), 9.42-9.46 (m, 1 H) 13

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N- [(2S)-1-hydroxypropan-2- yl]-3-oxo-2,3- dihydropyridazine- 4-carboxamide 6-[6-(Difluoromethyl)-3- pyridyl]-2-(3- fluorophenyl)-3- oxo-pyridazine-4-carboxylic acid; (S)-(+)-2-Amino-1- propanol (L- Alaninol) ¹H NMR (400MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 3.43-3.50 (m, 2 H), 3.98- 4.09 (m,1 H), 4.94-4.99 (m, 1 H), 6.90- 7.20 (m, 1 H), 7.36-7.43 (m, 1 H), 7.55-7.67 (m, 3 H), 7.84 (d, 1 H), 8.54-8.57 (m, 1 H), 8.74- 8.77 (m, 1 H),9.24-9.27 (m, 1 H), 9.38- 9.43 (m, 1 H) 14

2-(3- Fluorophenyl)-N- [(2S)-3-hydroxy- 3-methylbutan-2- yl]-3-oxo-6-[2-(trifluoromethyl) pyrimidin-5-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[2- (trifluoromethyl) pyrimidin-5-yl]pyridazine-4- carboxylic acid; (3S)-3-amino-2- methylbutan-2-olhydrochlorid ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.11 (s, 3 H), 1.14 (d,3 H), 1.16 (s, 3 H), 3.88-3.97 (m, 1 H), 4.61- 4.73 (m, 1 H), 7.36-7.44(m, 1 H), 7.60- 7.65 (m, 2 H), 7.66-7.71 (m, 1 H), 8.87 (s, 1 H), 9.46(d, 1 H), 9.62 (s, 2 H) 15

N-[(2S)-3,3- Difluoro-2- hydroxypropyl]-2- (3-fluorophenyl)- 3-oxo-6-[2-(trifluoromethyl) pyrimidin-5-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[2- (trifluoromethyl) pyrimidin-5-yl]pyridazine-4- carboxylic acid; (2S)-3-amino-1,1- difluoropropan-2- olhydrochlorid ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 3.38-3.46 (m, 1 H),3.61- 3.70 (m, 1 H), 3.79-3.93 (m, 1 H), 5.79- 6.09 (m, 1 H), 6.01 (brd, 1 H), 7.36-7.44 (m, 1 H), 7.59- 7.64 (m, 2 H), 7.69 (dt, 1 H), 8.88(s, 1 H), 9.50 (t, 1 H), 9.63 (s, 2 H) 16

2-(3- Fluorophenyl)-N- [(2S,3S)-3- hydroxybutan-2- yl]-3-oxo-6-[2-(trifluoromethyl) pyrimidin-5-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[2- (trifluoromethyl) pyrimidin-5-yl]pyridazine-4- carboxylic acid; (2S,3S)-3- aminobutan-2-olhydrochloride ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.05 (d, 3 H), 1.16 (d,3 H), 3.67-3.76 (m, 1 H), 3.90- 3.99 (m, 1 H), 4.97 (d, 1 H), 7.36-7.44(m, 1 H), 7.59- 7.65 (m, 2 H), 7.66-7.71 (m, 1 H), 8.87 (s, 1 H), 9.38(d, 1 H), 9.62 (s, 2 H) 17

2-(3- Fluorophenyl)-N- (2-hydroxy-2- methylpropyl)-3- oxo-6-[2-(trifluoromethyl) pyrimidin-5-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[2- (trifluoromethyl) pyrimidin-5-yl]pyridazine-4- carboxylic acid; 1- amino-2- methylpropan-2-ol ¹H NMR(400 MHz, DMSO- d₆) δ ppm = 1.13 (s, 6 H), 3.32 (br s, 2 H), 4.69 (s, 1H), 7.37-7.44 (m, 1 H), 7.60- 7.65 (m, 2 H), 7.67-7.72 (m, 1 H), 8.87(s, 1 H), 9.47 (t, 1 H), 9.63 (s, 2 H) 24

6-(5- Chloropyridin-2- yl)-2-(3- fluorophenyl)-N- [(2S)-1-hydroxypropan-2- yl]-3-oxo-2,3- dihydropyridazine- 4-carboxamide6-(5-Chloropyridin- 2-yl)-2-(3- fluorophenyl)-3- oxo-2,3-dihydropyridazine- 4-carboxylic acid; 1-amino-2- methylpropan-2-ol ¹HNMR (400 MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 3.40-3.49 (m, 2 H), 3.98-4.10 (m, 1 H), 4.94 (t, 1 H), 7.36-7.44 (m, 1 H), 7.54- 7.59 (m, 1 H),7.59-7.66 (m, 2 H), 8.06- 8.10 (m, 1 H), 8.12-8.16 (m, 1 H), 8.82 (dd, 1H), 9.02 (s, 1 H), 9.41 (d, 1 H) 25

2-(3- Fluorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[5-(trifluoromethyl) pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[5- (trifluoromethyl) pyridin-2-yl]-2,3-dihydropyridazine- 4-carboxylic acid; 1-amino-2- methylpropan-2-ol ¹HNMR (400 MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 3.42-3.49 (m, 2 H), 3.99-4.10 (m, 1 H), 4.95 (t, 1 H), 7.38-7.45 (m, 1 H), 7.56- 7.60 (m, 1 H),7.61-7.67 (m, 2 H), 8.29- 8.38 (m, 2 H), 9.08 (s, 1 H), 9.16-9.19 (m, 1H), 9.39 (d, 1 H) 26

2-(3- Fluorophenyl)-N- [(3S,4R)-4- hydroxytetrahydro thiophen-3-yl]-3-oxo-6-[6- (trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine-4-carboxamide 2-(3- Fluorophenyl)-3- oxo-6-[5- (trifluoromethyl)pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxylic acid; 1-amino-2-methylpropan-2-ol; (3R,4S)-4- aminotetrahydro thiophene-3-olhydrochloride ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 2.68- 2.76 (m, 2H),3.01-3.06 (m, 1H), 3.08-3.14 (m, 1H), 4.30- 4.39 (m s, 2H), 7.38-7.44(m, 1H), 7.56-7.69 (m, 3H), 8.05 (d, 1H), 8.63- 8.68 (m, 1H), 8.83 (s,1H), 9.35 (d, 1H), 9.76 (br d, 1H). 27

N-[(1S)-1- Cyclopropyl-2- hydroxy-2- methylpropyl]-6- [6-(difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3-dihydropyridazine- 4-carboxamide 6-[6- (Difluoromethyl)pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3- dihydropyridazine-4-carboxylic acid; (S)-1-amino-1- cyclopropyl-2- methylpropan-2-olhydrochloride (1:1) ¹H NMR (400 MHz, DMSO- d6) δ ppm = 0.27-0.39 (m, 3H), 0.51- 0.60 (m, 1 H), 1.10 (s, 3 H), 1.11-1.17 (m, 1 H), 1.28 (s, 3H), 4.70 (s, 1 H), 7.05 (t, 1 H), 7.36-7.43 (m, 1 H), 7.57- 7.70 (m, 3H), 7.83 (d, 1 H), 8.56 (dd, 1 H), 8.78 (s, 1 H), 9.26 (d, 1 H), 9.63(d, 1 H). 28

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2- yl]-2,3- dihydropyridazine-4-carboxamide 6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazine- 4-carboxylic acid;(2R)-2-amino- 3,3,3- trifluoropropan-1- ol hydrochloride (1:1) ¹H NMR(400 MHz, DMSO- d6) δ ppm = 3.65-3.75 (m, 1 H), 3.79- 3.87 (m, 1 H),4.79-4.92 (m, 1 H), 5.42- 5.46 (m, 1 H), 7.06 (t, 1 H), 7.38-7.45 (m, 1H), 7.57- 7.70 (m, 3 H), 7.84 (d, 1 H), 8.58 (dd, 1 H), 8.85 (s, 1 H),9.28 (d, 1 H), 9.97 (d, 1 H). 29

N-[(1S)-1- Cyclopropyl-2- hydroxyethyl]-6- [6- (difluoromethyl)pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3- dihydropyridazine-4-carboxamide 6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazine- 4-carboxylic acid;(2S)-2-amino-2- cyclopropylen-1-ol hydrochloride (1:1) ¹H NMR (400 MHz,DMSO- d6) δ ppm = 0.25-0.40 (m, 2 H), 0.40- 0.50 (m, 2 H), 1.03-1.14 (m,1 H), 3.40- 3.49 (m, 1 H), 3.53-3.63 (m, 2 H), 4.93 (t, 1 H), 7.06 (t, 1H), 7.37-7.44 (m, 1 H), 7.56- 7.69 (m, 3 H), 7.84 (d, 1 H), 8.56 (dd, 1H), 8.78 (s, 1 H), 9.26 (d, 1 H), 9.53 (d, 1 H). 30

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N- [(1S,2R)-2-hydroxycyclo- pentyl]-3-oxo-2,3- dihydropyridazine- 4-carboxamide 6-[6-(Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3-dihydropyridazine- 4-carboxylic acid; cis-(1R,2S)-2- aminocyclo pentanolhydrochloride (1:1) ¹H NMR (400 MHz, DMSO- d6) δ ppm = 1.47-1.65 (m, 3H), 1.68- 1.89 (m, 2 H), 1.92-2.03 (m, 1 H), 3.99- 4.12 (m, 2 H), 5.05(d, 1 H), 7.06 (t, 1 H), 7.36-7.43 (m, 1 H), 7.55- 7.67 (m, 3 H), 7.84(d, 1 H), 8.56 (dd, 1 H), 8.78 (s, 1 H), 9.26 (d, 1 H), 9.67 (d, 1 H).31

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N- [(1-hydroxycyclohexyl) methyl]-3-oxo- 2,3- dihydropyridazine- 4-carboxamide6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3-dihydropyridazine- 4-carboxylic acid; 1-aminomethyl-1- cyclohexanolhydrochloride (1:1) ¹H NMR (400 MHz, DMSO- d6) δ ppm = 1.18-1.62 (m, 10H), 3.35 (d, 2 H), 4.48 (s, 1 H), 7.06 (t, 1 H), 7.40 (ddd, 1 H),7.57-7.68 (m, 3 H), 7.84 (d, 1 H), 8.57 (dd, 1 H), 8.77 (s, 1 H), 9.26(d, 1 H), 9.51 (t, 1 H). 32

N-[(1S)-1-Cyano- 2-hydroxyethyl]-6- [6- (difluoromethyl)pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3- dihydropyridazine-4-carboxamide 6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazine- 4-carboxylic acid;(2S)-2-amino-3- hydroxypropane- nitril ¹H NMR (400 MHz, DMSO- d6) δ ppm= 3.71-3.86 (m, 2 H), 5.03- 5.08 (m, 1 H), 5.83 (t, 1 H), 7.06 (t, 1 H),7.37-7.44 (m, 1 H), 7.57- 7.70 (m, 3 H), 7.84 (d, 1 H), 8.59 (dd, 1 H),8.82 (s, 1 H), 9.29 (d, 1 H), 9.95 (d, 1 H). 33

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N- [(3S,4S)-4-hydroxyoxolan-3- yl]-3-oxo-2,3- dihydropyridazine- 4-carboxamide 6-[6-(Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3-dihydropyridazine- 4-carboxylic acid; (3S,4S)-4- aminotetrahydrofuran-3-ol ¹H NMR (400 MHz, DMSO- d6) δ ppm = 3.45 (t, 1 H), 3.62 (dd, 1H), 3.93 (dd, 1 H), 3.98-4.05 (m, 1 H), 4.25- 4.39 (m, 2 H), 5.70 (br s,1 H), 7.06 (t, 1 H), 7.33-7.43 (m, 1 H), 7.56- 7.68 (m, 3 H), 7.84 (d, 1H), 8.56 (dd, 1 H), 8.79 (s, 1 H), 9.26 (d, 1 H), 9.81 (d, 1 H). 34

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N-(2-hydroxy-2- methylpropyl)-3- oxo-2,3- dihydropyridazine- 4-carboxamide6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3-dihydropyridazine- 4-carboxylic acid; 1-amino-2- methylpropan-2-ol ¹HNMR (400 MHz, DMSO- d6) δ ppm = 1.13 (s, 6H), 3.31 (d, 2 H), 4.68 (s, 1H), 7.06 (t, 1 H), 7.36-7.43 (m, 1 H), 7.58- 7.68 (m, 3 H), 7.84 (d, 1H), 8.57 (dd, 1 H), 8.77 (s, 1 H), 9.26 (d, 1 H), 9.51 (t, 1 H) 35

1,5-Anhydro-2,4- dideoxy-2-[({6-[6- (difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazin- 4- yl}carbonyl)amino]-D-erythro- pentitol 6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazine- 4-carboxylic acid;2-amino-1,5- anhydro-2,4- dideoxy-D-erythro- pentitol hydrochloride(1:1) ¹H NMR (400 MHz, DMSO- d6) δ ppm = 1.58-1.67 (m, 1 H), 1.72- 1.82(m, 1 H), 3.47-3.54 (m, 1 H), 3.55- 3.59 (m, 2 H), 3.66-3.74 (m, 1 H),3.89- 3.95 (m, 1 H), 4.04-4.12 (m, 1 H), 5.23 (d, 1 H), 7.06 (t, 1 H),7.37-7.44 (m, 1 H), 7.55- 7.69 (m, 3 H), 7.84 (d, 1 H), 8.57 (dd, 1 H),8.79 (s, 1 H), 9.26 (d, 1 H), 9.66 (d, 1 H). 36

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N-[2-hydroxy-1- (tetrahydrofuran- 3-yl)ethyl]-3-oxo- 2,3-dihydropyridazine- 4-carboxamide 6-[6- (Difluoromethyl)pyridin-3-yl]-2-(3- fluorophenyl)-3- oxo-2,3- dihydropyridazine-4-carboxylic acid; 2-amino-2- (tetrahydrofuran-3- yl)ethanol ¹H NMR (400MHz, DMSO- d6) δ ppm = 1.57-1.72 (m, 1 H), 1.85- 2.03 (m, 1 H),3.39-3.64 (m, 4 H), 3.69- 3.83 (m, 2 H), 3.97-4.09 (m, 1 H), 4.95 (t, 1H), 7.05 (t, 1 H), 7.36-7.44 (m, 1 H), 7.57- 7.68 (m, 3 H), 7.84 (d, 1H), 8.57 (dd, 1 H), 8.77 (d, 1 H), 9.26 (d, 1 H), 9.47-9.54 (m, 1 H). 37

1,5-Anhydro-2,4- dideoxy-2-[({6-[6- (difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazin- 4-yl} carbonyl)amino]-L-threo-pentitol 6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazine- 4-carboxylic acid;(3S,4S)-3-amino- 4-hydroxy- tetrahydropyran ¹H NMR (400 MHz, DMSO- d6) δppm = 1.44-1.53 (m, 1 H), 1.87 (ddd, 1 H), 3.20- 3.27 (m, 1 H),3.41-3.48 (m, 1 H), 3.62- 3.70 (m, 1 H), 3.74-3.828 (m, 2 H), 3.94 (dd,1 H), 5.20 (br s, 1 H), 7.06 (t, 1 H), 7.37- 7.44 (m, 1 H), 7.57-7.68(m, 3 H), 7.84 (d, 1 H), 8.57 (dd, 1 H), 8.78 (s, 1 H), 9.27 (d, 1 H),9.52 (d, 1 H). 38

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N- [(3S,4R)-4-hydroxytetrahydro furan-3-yl]-3-oxo- 2,3- dihydropyridazine-4-carboxamide 6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3-fluorophenyl)-3- oxo-2,3- dihydropyridazine- 4-carboxylic acid;(3R,4S)-4-amino- tetrahydrofuran-3- ol ¹H NMR (400 MHz, DMSO- d6) δ ppm= 3.54 (dd, 1 H), 3.65 (dd, 1 H), 3.90 (dd, 1 H), 3.98 (dd, 1 H),4.16-4.20 (m, 1 H), 4.23- 4.28 (m, 1 H), 5.50 (d, 1 H), 7.06 (t, 1 H),7.36-7.43 (m, 1 H), 7.56- 7.67 (m, 3 H), 7.84 (d, 1 H), 8.57 (dd, 1 H),8.75 (s, 1 H), 9.27 (d, 1 H), 9.41 (d, 1 H). 39

N-[(1S)-1-Cyano- 2-hydroxyethyl]-2- (3-fluorophenyl)- 3-oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide2-(3- Fluorophenyl)-3- oxo-6-[6- (trifluoromethyl) pyridin-3-yl]-2,3-dihydropyridazine- 4-carboxylic acid; (2S)-2-amino-3- hydroxypropanenitrile hydrochloride (1:1) ¹H NMR (400 MHz, DMSO- d6) δ ppm = 3.72-3.85(m, 2 H), 5.03- 5.09 (m, 1 H), 5.83 (t, 1 H), 7.38-7.45 (m, 1 H), 7.57-7.72 (m, 3 H), 8.05 (d, 1 H), 8.67 (dd, 1 H), 8.85 (s, 1 H), 9.37 (d, 1H), 9.93 (d, 1 H). 40

1,5-anhydro-2,4- dideoxy-2-[({2-(3- fluorophenyl)-3- oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazin- 4-yl}carbonyl)amino]- D-erythro- pentitol 2-(3- Fluorophenyl)-3- oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxylicacid; (3S,4R)-3- aminooxan-4-ol hydrochloride (1:1) ¹H NMR (400 MHz,DMSO- d6) δ ppm = 1.57-1.68 (m, 1 H), 1.73- 1.82 (m, 1 H), 3.46-3.54 (m,1 H), 3.56 (d, 2 H), 3.66-3.74 (m, 1 H), 3.90- 3.96 (m, 1 H), 4.03-4.12(m, 1 H), 5.24 (d, 1 H), 7.37-7.44 (m, 1 H), 7.56- 7.69 (m, 3 H), 8.04(d, 1 H), 8.65 (dd, 1 H), 8.83 (s, 1 H), 9.35 (d, 1 H), 9.65 (d, 1 H).

The following examples were prepared from the starting materials statedin the table using the following procedure. Enantiomers were separatedfrom their racemate by chiral HPLC using the column and solventconditions stated.

A pyridazinone (1 eq.) was dissolved in acetonitrile followed by theaddition of molecular sieves (4 Å, powder), boronic acid or pinacolate(1.5 eq.), triethylamine (2 eq.), pyridine (2 eq.) and anhydrous copperdiacetate (2 eq.). The reaction mixture was stirred for 3 h at 80° C.,filtered, concentrated and purified by RP-HPLC (methods A-C depending onpolarity).

TABLE 3 Examples 18-23 Example structure IUPAC name Starting materialsanalytics 18

2-(3- Fluorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[6-(trifluoromethyl) pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamideN-[(2S)-1- Hydroxypropan-2- yl]-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3- dihydropyridazine- 4-carboxamide; 3- Fluorophenylboronic acid pinacol ester ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.17 (d, 3H), 3.40-3.51 (m, 2 H), 4.00- 4.09 (m, 1 H), 4.95 (t, 1 H), 7.37-7.44(m, 1 H), 7.56- 7.69 (m, 3 H), 8.03-8.07 (m, 1 H), 8.63- 8.67 (m, 1 H),8.79-8.81 (m, 1 H), 9.33- 9.36 (m, 1 H), 9.39 (d, 1 H) 19

6-[6- (Dimethylamino) pyridin-3-yl]-2-(3- fluorophenyl)-N-[(2R)-3-hydroxy- 3-methylbutan-2- yl]-3-oxo-2,3- dihydropyridazine-4-carboxamide 6-[6- (Dimethylamino) pyridin-3-yl]-N- [(2R)- 3-hydroxy-3-methylbutan-2-yl]- 3-oxo-2,3- dihydropyridazine- 4-carboxamide;(3-Fluorophenyl) boronic acid ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.09(s, 3 H), 1.12 (d, 3 H), 1.15 (s, 3 H), 3.09 (s, 6 H), 3.85-3.95 (m, 1H), 4.61- 4.66 (m, 1 H), 6.74 (d, 1 H), 7.30-7.42 (m, 1 H), 7.49- 7.66(m, 3 H), 8.03 (dd, 1 H), 8.59 (s, 1 H), 8.65 (d, 1 H), 9.59 (d, 1 H) 20

2-(3- Fluorophenyl)-N- [(2R)-3-hydroxy- 3-methylbutan-2- yl]-6-(6-methoxypyridin-3- yl)-3-oxo-2,3- dihydropyridazine- 4-carboxamideN-[(2R)-3- Hydroxy-3- methylbutan-2-yl]- 6-(6- methoxypyridin-3-yl)-3-oxo-2,3- dihydropyridazine- 4-carboxamide; (3-Fluorophenyl)boronic acid ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.10 (s, 3 H), 1.13 (d,3 H), 1.15 (s, 3 H), 3.87-3.95 (m, 4 H), 4.65 (s, 1 H), 6.93-6.98 (m, 1H), 7.34- 7.41 (m, 1 H), 7.53-7.65 (m, 3 H), 8.25 (dd, 1 H), 8.66 (s, 1H), 8.75-8.79 (m, 1 H), 9.55 (d, 1 H) 21

2-(3- Fluorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-6-(6-methoxypyridin-3- yl)-3-oxo-2,3- dihydropyridazine- 4-carboxamideN-[(2S)-1- Hydroxypropan-2- yl]-6-(6- methoxypyridin-3- yl)-3-oxo-2,3-dihydropyridazine- 4-carboxamide; (3-Fluorophenyl) boronic acid ¹H NMR(400 MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 3.40-3.49 (m, 2 H), 3.92 (s,3 H), 3.99-4.08 (m, 1 H), 4.93 (t, 1 H), 6.94- 6.97 (m, 1 H), 7.34-7.41(m, 1 H), 7.53- 7.65 (m, 3 H), 8.24-8.28 (m, 1 H), 8.65 (s, 1 H), 8.77(d, 1 H), 9.45 (d, 1 H) 22

6-[6- (Difluoromethyl) pyridin-3-yl]-2-(3- fluorophenyl)-N-[(2R)-3-hydroxy- 3-methylbutan-2- yl]-3-oxo-2,3- dihydropyridazine-4-carboxamide 6-[6- (Difluoromethyl) pyridin-3-yl]- N-[(2R)-3-hydroxy-3- methylbutan-2-yl]- 3-oxo-2,3- dihydropyridazine-4-carboxamide; (3-Fluorophenyl) boronic acid ¹H NMR (400 MHz, DMSO- d₆)δ ppm = 1.10 (s, 3 H), 1.13 (d, 3 H), 1.16 (s, 3 H), 3.88-3.97 (m, 1 H),4.66 (s, 1 H), 7.05 (t, 1 H), 7.37-7.43 (m, 1 H), 7.56- 7.68 (m, 3 H),7.83 (d, 1 H), 8.56 (dd, 1 H), 8.77 (s, 1 H), 9.25-9.27 (m, 1 H), 9.51(d, 1 H) 23

2-(3- Fluorophenyl)-N- [(2S)-1- hydroxypropan-2- yl]-6-(6-methylpyridin-3- yl)-3-oxo-2,3- dihydropyridazine- 4-carboxamideN-[(2S)-1- Hydroxypropan-2- yl]-6-(6- methylpyridin-3- yl)-3-oxo-2,3-dihydropyridazine- 4-carboxamide; 3- Fluorophenyl boronic acid pinacolester ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 2.54 (s, 3 H),3.40-3.50 (m, 2 H), 3.98- 4.08 (m, 1 H), 4.94 (t, 1 H), 7.35-7.43 (m, 2H), 7.54- 7.67 (m, 3 H), 8.24 (dd, 1 H), 8.67 (s, 1 H), 9.00 (d, 1 H),9.43 (d, 1 H) 41

2-(3,5- Difluorophenyl)- N-[(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[5-(trifluoromethyl) pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxamideN-[(2S)-1- Hydroxypropan-2- yl]-3-oxo-6-[5- (trifluoromethyl)pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxamide; (3,5-difluorophenyl) boronic acid ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.16 (d,3 H), 3.43-3.49 (m, 2 H), 3.99- 4.10 (m, 1 H), 4.97 (t br, 1 H),7.47-7.55 (m, 1 H), 7.55- 7.63 (m, 2 H), 8.32-8.40 (m, 2 H), 9.07 (s, 1H), 9.16-9.20 (m, 1 H), 9.33 (d, 1 H). 42

N-[(2S)-1- Hydroxypropan-2- yl]-3-oxo-2- phenyl-6-[5- (trifluoromethyl)pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxamide N-[(2S)-1-Hydroxypropan-2- yl]-3-oxo-6-[5- (trifluoromethyl) pyridin-2-yl]-2,3-dihydropyridazine- 4-carboxamide; phenyl boronic acid pinacol ester ¹HNMR (400 MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 3.40-3.49 (m, 2 H), 3.99-4.10 (m, 1 H), 4.95 (t, 1 H), 7.50-7.62 (m, 3 H), 7.67- 7.71 (m, 2 H),8.27-8.31 (m, 1 H), 8.32- 8.37 (m, 1 H), 9.09 (s, 1 H), 9.16-9.18 (m, 1H), 9.44 (d, 1 H). 43

2-(3,4- Difluorophenyl)- N-[(2S)-1- hydroxypropan-2- yl]-3-oxo-6-[5-(trifluoromethyl) pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxamideN-[(2S)-1- Hydroxypropan-2- yl]-3-oxo-6-[5- (trifluoromethyl)pyridin-2-yl]-2,3- dihydropyridazine- 4-carboxamide; 3,4-difluorophenylboronic acid ¹H NMR (400 MHz, DMSO- d₆) δ ppm = 1.16 (d, 3 H), 3.41-3.49(m, 2 H), 3.97- 4.10 (m, 1 H), 4.96 (t, 1 H), 7.58-7.74 (m, 2 H), 7.93(ddd, 1 H), 8.31 (d, 1 H), 8.37 (dd, 1 H), 9.08 (s, 1 H), 9.15-9.20 (m,1 H), 9.38 (d, 1 H).

Experimental Section—Biological Assays

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

The in vitro activity of the compounds of the present invention can bedemonstrated in the following assays:

Transactivation Assay in Human Cell Line (In Vitro Assays 1 and 2)

Transactivation assays were carried out in U87 glioblastoma cells (ATCC)endogenously expressing AHR. In addition the cells were stablytransfected with an AHR inducible firefly luciferase reporter geneconstruct that carried AHR-binding sites (DRE) in its promoter and arenilla reporter gene construct with constitutively active promoter.Kynurenic acid is an endogenous AHR activating ligand and was used toprestimulate test cells prior to testing the antagonistic properties ofcompounds.

In Vitro Assay 1: Antagonism in Human Cell Line

Cells in medium (tryptophan free RPMI, 1% FCS, 2 mM Glutamine)supplemented with 150 μM kynurenic acid were grown for 20 hours inabsence (negative control) or presence of increasing concentrations oftest compounds (typical dilutions: 72 pmol/L, 0.25 nmol/L, 0.89 nmol/L;3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130 nmol/L, 470 nmol/L, 1.6 μmol/L,5.7 μmol/L and 20 μmol/L in duplicates). As positive inhibition controlcells supplemented with 150 μM kynurenic acid were incubated in presenceof 5 μM Staurosporin. Normalization was done by positive and negativecontrols.

Firefly luciferase and Renilla activity was determined by the DualGloLuciferase Assay System (Promega, #2920). Renilla activity was used toassess toxic effects of compounds.

In Vitro Assay 2: Agonism in Human Cell Line

Cells in medium (tryptophan free RPMI, 1% FCS, 2 mM Glutamine) weregrown for 20 hours in absence (negative control) or presence ofincreasing concentrations of test compounds (typical dilutions: 72pmol/L, 0.25 nmol/L, 0.89 nmol/L; 3.1 nmol/L, 11 nmol/L, 38 nmol/L, 130nmol/L, 470 nmol/L, 1.6 μmol/L, 5.7 μmol/L and 20 μmol/L in duplicates).As positive activation control cells were incubated with 300 μMkynurenic acid. Normalization was done by positive and negativecontrols.

Firefly luciferase activity was determined by the SteadyGlo LuciferaseAssay System (Promega, #2520).

In Vitro Assay 3: AHR-Regulated CYP1A1 Expression in Human Cell Line

To assess the AHR inhibitory activity of the substances described inthis application, the ability thereof to antagonise ligand-induced AHRgene regulation in a dose-dependent manner was quantified. For thispurpose, quantitative PCR analysis was used to determine expression ofthe AHR-regulated gene CYP1A1 in a human monocytic U937 cell line uponstimulation with 200 μM KA in the presence and absence of AHR inhibitor.U937 cells were sown at a concentration of 2×10⁵ cells/well in 100 μl ofgrowth medium (RPMI 1640, 20% FCS) in 96-well microtitre plates. CYP1A1expression was induced with 200 μM KA (positive control) in the presenceor absence of the substances for 6 hours. Human U937 cells weretypically incubated with eight different concentrations of thesubstances (1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM and 3 μM) andanalyzed in duplicate on the same microtitre plate. After stimulation,cells were lysed with Nucleic Acid Lysis Solution (# 4305895, AppliedBiosystems) and RNA was isolated using the 6100 Nucleic Acid PreparationStation (Applied Biosystems) and reverse-transcribed to cDNA usingSuperScript VILO cDNA synthesis kit (# 11754-250, Invitrogen).Unstimulated cells were used as the negative control. Taqman probes forhuman CYP1A1 (Hs01054797_g1) and human HPRT (Hs02800695_m1) were used toanalyze fold expression of CYP1A1 of HPRT. Quantitation was performed ona Taqman SDS7900HT.

TABLE 4 IC₅₀ values of examples in in vitro assays 1-3 Assay 1: Assay 2:Assay 3: AHR-luc Hum AHR-luc Hum Hum CYP1A1 Antagonism AgonismAntagonism Example IC₅₀ [M] IC₅₀ [M] IC₅₀ [M] 1 7.14E−9 >2.00E−5 5.29E−92 2.35E−8 >2.00E−5 3.68E−8 3 6.23E−7 >2.00E−5 4 1.28E−7 >2.00E−5 2.22E−75 1.63E−7 >2.00E−5 2.81E−7 6 1.34E−8 >2.00E−5 8.32E−9 7 2.58E−8 >2.00E−54.81E−8 8 6.28E−9  1.11E−5 1.03E−8 9 1.62E−8 >2.00E−5 2.53E−8 107.32E−8 >2.00E−5 1.10E−7 11 4.95E−7 >2.00E−5 3.26E−7 12 1.08E−6 >2.00E−513 1.57E−7 >2.00E−5 1.98E−7 14 2.17E−7 >2.00E−5 15 3.07E−7 >2.00E−5 161.69E−7 >2.00E−5 17 2.03E−6 >2.00E−5 18 3.38E−8 >2.00E−5 3.14E−8 199.19E−8 >2.00E−5 1.47E−7 20 5.09E−7 >2.00E−5 21 1.28E−7 >2.00E−5 4.40E−722 6.26E−8 >2.00E−5 1.86E−7 23 2.65E−7 >2.00E−5 24 3.52E−7 >2.00E−5 258.48E−8 >2.00E−5 26 5.74E−6  5.97E−6 27 4.08E−9  1.53E−5 28 6.65E−9 1.57E−5 29 1.51E−8 >2.00E−5 30 2.18E−8 >2.00E−5 31 3.18E−8 >2.00E−5 325.59E−8 >2.00E−5 33 7.51E−8 >2.00E−5 34 1.56E−7 >2.00E−5 351.74E−7 >2.00E−5 36 1.96E−7 >2.00E−5 37 2.68E−7 >2.00E−5 383.70E−7 >2.00E−5 39 2.28E−8 >2.00E−5 40 3.28E−8 >2.00E−5 419.65E−8 >2.00E−5 42 3.86E−7 >2.00E−5 43 9.02E−7

1. A compound of formula (I):

wherein X is CH or N; Y is CR³ or N; Z is CH or N, wherein if X is N, Yis CR³ and Z is CH, and if X is CH, Y is N and Z is CH, and if Z is N, Yis N, X is CH and R² is trifluoromethyl; R¹ is C₂-C₈-hydroxyalkyl,wherein said C₂-C₈-hydroxyalkyl groups are optionally substituted oncewith R⁷ and optionally one to three times with halogen, orC₃-C₆-cycloalkyl substituted once with hydroxy or C₁-C₃-hydroxyalkyl andoptionally one to three times with halogen, or (C₃-C₆-cycloalkylsubstituted once with hydroxy)-C₁-C₄-alkyl, or 4- to 6-memberedheterocycloalkyl substituted once with hydroxy or C₁-C₃-hydroxyalkyl andoptionally one to three times with halogen, or (4- to 6-memberedheterocycloalkyl substituted once with hydroxy)-C₁-C₄-alkyl; R² ischloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,difluoromethoxy, trifluoromethoxy or —NR⁸R⁹; R³ is hydrogen, halogen ormethyl; R⁴ is hydrogen, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, halogen or cyano; R⁵ is hydrogen or halogen; R⁶ ishydrogen or halogen; R⁷ is C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, 4- to6-membered heterocycloalkyl, —CO₂—R¹⁰, —CO—NR⁸R⁹, cyano or —NR⁸R⁹; R⁸and R⁹ are the same or different and are, independently from each other,hydrogen or C₁-C₃-alkyl, or together with the nitrogen atom to whichthey are attached form a 4- to 6-membered nitrogen containingheterocyclic ring, said ring optionally containing one additionalheteroatom selected from the group consisting of O, S, NH, and NR^(a) inwhich R^(a) is a C₁-C₄-alkyl group; and R¹⁰ is hydrogen or C₁-C₄-alkyl;or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer,an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt,a solvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing.
 2. The compound according to claim 1, wherein: Xis CH or N; Y is CR³ or N; Z is CH or N, wherein if X is N, Y is CR³ andZ is CH, and if X is CH, Y is N and Z is CH, and if Z is N, Y is N, X isCH and R² is trifluoromethyl; R¹ is C₂-C₆-hydroxyalkyl, wherein saidC₂-C₆-hydroxyalkyl groups are optionally substituted once with R⁷ andoptionally one to three times with fluoro or chloro, or C₃-C₆-cycloalkylsubstituted once with hydroxy, or 4- to 6-membered heterocycloalkylsubstituted once with hydroxy; R² is chloro, methyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,trifluoromethoxy or —NR⁸R⁹; R³ is hydrogen or methyl; R⁴ is hydrogen,fluoro or chloro; R⁵ is hydrogen or fluoro; R⁶ is hydrogen or fluoro; R⁷is methoxy, cyclopropyl or tetrahydrofuranyl; R⁸ and R⁹ are the same ordifferent and are, independently from each other, hydrogen or methyl; ora polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, anN-oxide, a hydrate, or a solvate, a physiologically acceptable salt, asolvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing.
 3. The compound according to claim 1, wherein: Xis CH or N; Y is CR³ or N; Z is CH or N, wherein if X is N, Y is CR³ andZ is CH, and if X is CH, Y is N and Z is CH, and if Z is N, Y is N, X isCH and R² is trifluoromethyl; R¹ is C₃-C₅-hydroxyalkyl, wherein saidC₃-C₅-hydroxyalkyl groups are optionally substituted one to three timeswith fluoro, or cyclopentyl substituted once with hydroxy, ortetrahydrothiophenyl substituted once with hydroxy; R² is methyl,difluoromethyl, trifluoromethyl, methoxy or —NR⁸R⁹; R³ is hydrogen; R⁴is hydrogen, fluoro or chloro; R⁵ is hydrogen or fluoro; R⁶ is hydrogenor fluoro; R⁸ and R⁹ represent are each methyl; or a polymorph, anenantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, ahydrate, or a solvate, a physiologically acceptable salt, a solvate of aphysiologically acceptable salt thereof, or a mixture of any of theforegoing.
 4. The compound according to claim 1, which is selected fromthe group consisting of2-(3,5-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Chloro-5-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3,4-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;N-[(2S)-1-Hydroxypropan-2-yl]-3-oxo-2-phenyl-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(1S,2S)-2-hydroxycyclopentyl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide:,2-(3-Fluorophenyl)-N-[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(5-methylpyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;N-[(2S)-3,3-Difluoro-2-hydroxypropyl]-2-(3-fluorophenyl)-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S,3S)-3-hydroxybutan-2-yl]-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;6-[6-(Dimethylamino)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-6-(6-methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(6-methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(6-methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-(5-Chloropyridin-2-yl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide;2-(3-Fluorophenyl)-N-[(3S,4R)-4-hydroxytetrahydrothiophen-3-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;N-[(1S)-1-Cyclopropyl-2-hydroxy-2-methylpropyl]-6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide;N-[(1S)-1-Cyclopropyl-2-hydroxyethyl]-6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-Dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(1-hydroxycyclohexyl)methyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;N-[(1S)-1-Cyano-2-hydroxyethyl]-6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(3S,4S)-4-hydroxyoxolan-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;1,5-Anhydro-2,4-dideoxy-2-[({6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl}carbonyl)amino]-D-erythro-pentitol;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[2-hydroxy-1-(tetrahydrofuran-3-yl)ethyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;1,5-Anhydro-2,4-dideoxy-2-[({6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl}carbonyl)amino]-L-threo-pentitol;6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;N-[(1S)-1-Cyano-2-hydroxyethyl]-2-(3-fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;1,5-Anhydro-2,4-dideoxy-2-[({2-(3-fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazin-4-yl}carbonyl)amino]-D-erythro-pentitol;2-(3,5-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide;N-[(2S)-1-Hydroxypropan-2-yl]-3-oxo-2-phenyl-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide;and2-(3,4-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide:or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer,an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt,a solvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing.
 5. A method of preparing a compound of formula (I)according to claim 1, said method comprising the step of reacting anintermediate compound of formula (VII):

in which R², R⁴, R⁵, R⁶, X, Y and Z are as defined for the compound offormula (I) according to claim 1, with a compound of formula (VIII):H2N—R¹   (III), in which R¹ is as defined for the compound of formula(I) according to claim 1, thereby giving a compound of formula (I):

in which R¹, R², R⁴, R⁵, R⁶, X, Y and Z are as defined for the compoundof formula (I) according to claim
 1. 6. (canceled)
 7. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 1,or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer,an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt,a solvate of a physiologically acceptable salt thereof, or a mixture ofany of the foregoing, and one or more pharmaceutically acceptableexcipients.
 8. A pharmaceutical combination comprising: one or morecompounds of formula (I) according to claim 1, or a polymorph, anenantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, ahydrate, or a solvate, a physiologically acceptable salt, a solvate of aphysiologically acceptable salt thereof, or a mixture of any of theforegoing, and one or more pharmaceutically active anti cancer compoundsor one or more pharmaceutically active immune checkpoint inhibitors. 9.A method for treatment or prophylaxis of a disease, comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1, or a polymorph, an enantiomer, adiastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or asolvate, a physiologically acceptable salt, a solvate of aphysiologically acceptable salt thereof, or a mixture of any of theforegoing, to a subject in need thereof.
 10. (canceled)
 11. The methodaccording to claim 9, wherein the disease is a cancer or a conditionwith dysregulated immune responses or a disorder associated withaberrant AHR signaling. cm
 12. A compound of formula (VII):

in which R², R⁴, R⁵, R⁶, X, Y and Z are as defined for the compound offormula (I) according to claim
 1. 13. (canceled)
 14. The methodaccording to claim 9, wherein the disease is a liquid tumour or a solidtumour.